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Neuroscience and Biobehavioral Reviews 36 (2012) 11631178

Contents lists available at SciVerse ScienceDirect

Neuroscience and Biobehavioral Reviews

jou rna l h omepa ge: www.elsev ier .com/ locate /neubiorev

eview

ognitive intervention in amnestic Mild Cognitive Impairment: A systematiceview

haron Sanz Simon , Juliana Emy Yokomizo, Cssio M.C. Bottinold Age Research Group (PROTER), Department and Institute of Psychiatry, Faculty of Medicine, University of So Paulo, SP, Brazil

r t i c l e i n f o

rticle history:eceived 27 August 2011eceived in revised form 13 January 2012ccepted 24 January 2012

eywords:gingild Cognitive Impairmentemoryeuropsychologyognitive interventions

a b s t r a c t

Mild Cognitive Impairment (MCI) represents a transitional state between normal aging and early demen-tia and is commonly associated with memory impairment (amnestic or A-MCI). Several studies haveinvestigated therapeutic approaches to A-MCI, including cholinestherase inhibitors (I-ChEs), althoughthis practice is still controversial. Thus, there is a current need to determine the effects of cognitiveinterventions either in combination with I-ChEs or alone. To assess the efficacy of such treatments, neu-ropsychological instruments and self-evaluated scoring of memory, mood, daily life activities and qualityof life are employed. Recently, some studies have used functional magnetic resonance imaging (fMRI) inorder to understand the neurobiological effects of these interventions. The aim of this systematic review isto investigate the effectiveness of cognitive interventions on the enhancement of learning abilities as wellas their impacts on cognitive measurements of mood, everyday functioning and functional neuroimaging.rainingehabilitationunctional neuroimaging

This review also focused on the methodological aspects of such studies and attempted to introduce newperspectives on cognitive interventions in this population. The authors concluded that a-MCI patientsare capable to learn new information and memory strategies. Although findings in standardized neu-ropsychological tests are limited, non-standardized cognitive measures and subjective measures showsignificant changes. Furthermore, fMRI reveals changes in the patterns of brain activation and increaseof connectivity. 2012 Elsevier Ltd. All rights reserved.

ontents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11641.1. Neuronal and cognitive plasticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11641.2. Cognitive reserve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11641.3. Approaches in cognitive interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11641.4. Functional neuroimaging and cognitive interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1164

2. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11653. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1165

3.1. What kind of cognitive interventions have been applied to A-MCI patients? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11653.2. Can cognitive intervention effects be generalized to objective cognitive measurements? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11693.3. Can cognitive interventions improve subjective measurements? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11693.4. Can the benefits of cognitive interventions be maintained during the follow-up period? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11733.5. Can fMRI identify the effects of cognitive interventions in A-MCI patients?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1173

4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1174

5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Corresponding author at: Old Age Research Group (PROTER), Institute of Psychiatry, Frd floor, 05403-010 - So Paulo, SP, Brazil. Tel.: +55 11 26618018.

E-mail addresses: [email protected] (S.S. Simon), julianayokomizo@yahoo

149-7634/$ see front matter 2012 Elsevier Ltd. All rights reserved.oi:10.1016/j.neubiorev.2012.01.007 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1176. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1176

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1176

aculty of Medicine, University of So Paulo. Rua Dr. Ovdio Pires de Campos, 785,

.com.br (J.E. Yokomizo), [email protected] (C.M.C. Bottino).

dx.doi.org/10.1016/j.neubiorev.2012.01.007http://www.sciencedirect.com/science/journal/01497634http://www.elsevier.com/locate/neubiorevmailto:[email protected]:[email protected]:[email protected]/10.1016/j.neubiorev.2012.01.007

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164 S.S. Simon et al. / Neuroscience and Bi

. Introduction

Mild Cognitive Impairment (MCI) often represents a transi-ional state between normal aging and early dementia, specially,lzheimers disease (Petersen et al., 1999). Although MCI remains

controversial diagnosis, the most commonly used criteria arehose for the amnestic form of MCI (A-MCI) (Petersen et al., 2001;etersen, 2004), which include memory complaints, objectiveemory deficits and relatively preserved cognitive and functionalbilities in the absence of the clinical criteria for dementia. Moreecently, new criteria have been published (Albert et al., 2011) thatmphasize the preservation of independence in daily life activi-ies, even when slight problems in the performance of complexreviously habitual tasks occur.According to a population-based epidemiological study

Gauthier et al., 2006), the prevalence of MCI ranges from 3% to9% in adults older than 65 years; some of these individuals seemo remain stable or return to normal over time, but more than halfrogress to dementia within 5 years. Additionally, a meta-analysisdentified an annual conversion rate of 510% of MCI patients toementia (Mitchell and Shiri-Freshki, 2009). However, these ratesaried between 12% and 15% depending on the methodology usedn each study (Morris et al., 2001; Ritchie et al., 2001; Tabert et al.,006).Considering these data, it seems crucial to develop and evaluate

harmacological and non-pharmacological treatment strategies forhis population. However, pharmacological treatment of individu-ls with MCI has been a controversial topic. A recent systematiceview did not report convincing effects in delayed disease pro-ression or conversion to dementia in MCI patients treated withholinesterase inhibitors (I-ChEs), and the authors reported impor-ant risks associated with the I-ChE treatment (Raschetti et al.,007). On the other hand, a meta-analysis demonstrated that theong-term use of I-ChE in subjects with MCI may attenuate theisk of progression to Alzheimers disease (AD)/dementia (Dinizt al., 2009). However, researchers concluded that currently, noffective pharmacological treatments exist for MCI patients (Aisen,008), especially with regard to long-term beneficial effects. Aecent review recommends engagement of MCI persons in cog-itive activities and participation in social activities, given thathese might be beneficial and pose little risk (Petersen, 2011).ence, non-pharmacological cognitive interventions are an emerg-ng therapeutic approach for the MCI patient population.

.1. Neuronal and cognitive plasticity

Neuronal plasticity is the nervous systems ability to adapt itstructural organization in response to changes in the environment,s well as other factors, such as injury (Buonomano and Merzenich,998). This process endows animals, especially humans and otherrimates, with the capacity to adapt to new cognitive or behavioraltresses (Rapoport, 1990). Similarly, cognitive plasticity refers tohanged patterns of cognitive behavior (e.g., decreased suscepti-ility to distractions) that depend on neural plasticity mechanismsGreenwood and Parasuraman, 2010). Researchers reported thathe presence of cognitive plasticity in individuals with MCI, as mea-ured by learning potential, is associated with less marked cognitiveecline (Calero and Navarro, 2004; Fernndez-Ballesteros et al.,005), which suggests that despite their cognitive deficits, MCIatients have some preserved abilities to learn new informationnd adapt their behaviors. Moreover, a recent meta-analysis has

rovided evidence that cognitive training programs can attenuatehe risk of cognitive decline in healthy elderly patients (Valenzueland Sachdev, 2009), which is thought to reflect increases in cogni-ion.vioral Reviews 36 (2012) 11631178

1.2. Cognitive reserve

Cognitive reserve is an important aspect in cognitive interven-tions because it describes the existence of brain mechanisms ableto cope with cerebral damage by using pre-existing or compen-satory cognitive processes (Stern, 2002). A meta-analysis includingover 29,000 individuals showed that people with high cognitivereserve had a 46% reduced risk of developing dementia compared toindividuals with low cognitive reserve. This effect persisted over amedian 7.1-year follow-up period (Valenzuela and Sachdev, 2006).The authors described several factors associated with increasedcognitive reserve, such as educational level (a critical topic indeveloping and underdeveloped countries), occupational attain-ment, premorbid intelligence quotient, leisure and cognitively andmentally stimulating activities, which are all relevant aspects toconsider in cognitive intervention programs. Hence, similar to ADfindings, higher cognitive reserve was associated with reducedbrain volumes in MCI patients, which represents more severe neu-ropathological processes (Sol-Padduls et al., 2009).

1.3. Approaches in cognitive interventions

Different approaches have been identified in a literature reviewof cognitive interventions and dementia (Clare et al., 2003). Cog-nitive stimulation comprises involvement in group activities thatare designed to increase cognitive and social functioning in a non-specific manner. By contrast, cognitive training is a more specificapproach, which teaches theoretically supported strategies andskills to optimize specific cognitive functions. Cognitive rehabilita-tion involves an individualized approach using tailored programscentered on specific activities of daily life. Personally relevant goalsare identified, and the therapist, patient and family work togetherto achieve these goals (e.g., joining a social group).

Moreover, a separate review also identified different categoriesof strategies that can be used separately or in combination toimprove cognitive abilities (Sitzer et al., 2006). Restorative strate-gies involve enhancing the functions of specific cognitive domains,with the goal of returning cognition to a previous level. On the otherhand, compensatory strategies teach patients new ways of perform-ing cognitive tasks and involves the use of internal and externalstrategies (Box 1 ).

In healthy elderly individuals, cognitive training is the moststudied approach and includes both restorative and compensatorystrategies. Several studies have shown improvements in the cog-nitive domains targeted by this type of training (Ball et al., 2002;Baltes et al., 1989; Stigsdotter and Bckman, 1992; Willis et al.,2006) and maintenance of these effects during 5-year follow-upperiod (Oswald et al., 1996; Willis et al., 2006).

1.4. Functional neuroimaging and cognitive interventions

Functional neuroimaging may be an important source ofinformation about the effects of cognitive interventions, as neu-roimaging can determine the intervention mechanisms at thecognitive and neural levels, possibly showing changes in the pat-terns of brain activation. Increased brain activation followingcognitive training in areas that were not previously activated wouldindicate a reliance on new, alternative strategies (Lustig et al.,2009). This tool has been successfully applied to evaluate the effectsof cognitive interventions in people with brain injuries (Laatschet al., 2004; Laatsch and Kritsky, 2006), although there have beenfew studies in older adults. One report found that healthy adults

of various ages, after using a mnemonic based on visual imagery,showed increased activation in the left parietaloccipital cortex,which is involved in visual imagery (Nyberg et al., 2003). More-over, functional neuroimaging data are valuable for monitoring

S.S. Simon et al. / Neuroscience and Biobeha

Box 1: Compensatory and restorative strategies.Compensatory strategies

Visual imagery (Breuil et al., 1994): association of verbalmaterial and visual information. Mental images are createdto facilitate the learning and recall of material

Method of loci (Londos et al., 2008): linking mentally a placewith each item to be remembered

Mind mapping (Londos et al., 2008): associations around acentral word or an idea are made using a diagram

Categorization and organization (Belleville et al., 2006): clas-sifying the information to learn by semantic category andorder of importance, respectively

Chunking (Belleville et al., 2006): grouping the informationto be remembered

Cueing (Belleville et al., 2006): prompting the recall perfor-mances using phonological and/or semantic cues

Memory aids (Wilson, 1999): notebook, notes system, calen-dars and prompts

Restorative strategies

Errorless learning (Wilson et al., 1994): elimination of incor-rect or inappropriate responses interferences) during thelearning process

Spaced retrieval (Landauer and Bjrk, 1978): repeated recall-ing of information at short but gradually increasing timeintervals

Vanishing cues (Glisky et al., 1986): the information is repeat-edly presented with diminishing intensity

Reality orientation therapy (Taulbee and Folsom, 1966): con-tinually presentation of orienting information (name, date,time, location, weather and current events)

Reminiscence therapy (Boylin et al., 1976): discussion ofremote events in order to place ones life in perspective.

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ubtle changes once a patients performance on less sensitive stan-ardized neuropsychological tests shows few changes followingognition-based interventions (Baltes et al., 1989). Although recenttudies using fMRI have been completed in A-MCI patients, thisopic has never been properly reviewed.

To date, several reviews (Belleville, 2008; Buschert et al., 2010;ean et al., 2010a; Scott and Spector, 2010) and a meta-analysis (Lit al., 2010) have reported beneficial effects, especially in memory,or cognitive interventions in MCI subjects, despite the method-logical limitations and the difficulty in comparing programs dueo the heterogeneity of the interventions. However, some criticaloints remain unclear, and the present systematic review intendso address the following questions:

A) What kind of cognitive interventions have been applied to A-MCI patients?

B) Can cognitive intervention effects be generalized to objectivecognitive measures?

C) Can cognitive interventions improve subjective measures?D) Can cognitive intervention benefits be maintained during the

follow-up period?E) Can fMRI identify the treatment effects of cognitive interven-

tions in A-MCI patients?

. MethodsInformation from January 1990 through March 2011 containedn the Medical Literature Analysis and Retrieval System (MED-INE) and the Excerpta Medica Database (EMBASE) were searchedvioral Reviews 36 (2012) 11631178 1165

using the following key terms in combination with mild cognitiveimpairment: neuropsychological rehabilitation, cognitive reha-bilitation, cognitive training, memory rehabilitation, memorytraining and neuroimaging.

Articles were selected for the present review if they met thefollowing inclusion criteria: (1) the study primarily evaluated theeffects of the cognitive intervention; (2) the patient sample metPetersens criteria for A-MCI (e.g. Petersen et al., 2001); (3) cognitiveassessments were completed pre- and post-intervention; and (4)articles were available in English, French, Spanish or Portuguese.There were no exclusion criteria because the aim of this literaturereview was to provide an overview of the cognitive interventionsthat have been studied to date.

3. Results

Twenty articles met the inclusion criteria and are described inTable 1. Five further studies were initially considered but werefinally rejected because they did not specify the A-MCI criteria used(Cipriani et al., 2006), did not use the Petersen Criteria for A-MCI(Gunther et al., 2003; Olazaran et al., 2004), did not present specificresults for the A-MCI group (Poon et al., 2005) or did not collect finaldata (Vidovich et al., 2009). The results were organized accordingto the questions stated above.

3.1. What kind of cognitive interventions have been applied toA-MCI patients?

Cognitive intervention programs varied considerably regardingtheir experimental designs (only 37% were randomized, controlledtrials) and sample size (1193). However, 90% of studies includedup to 30 A-MCI patients in the experimental group. Regardingpatient education, 82% of studies reported an average school edu-cation equal to or greater than 12 years; however, three studieslacked this information. An equal number of studies were com-pleted in individual or group settings, with considerable variationsas to the number (120, with 75% reporting 12 sessions or less) andduration of sessions (45150 min).

All programs targeted episodic memory because the studiesfocused on individuals with A-MCI. However, some interventionsalso involved attention, speed of processing, language, visual-spatial abilities and executive functions (Kurz et al., 2009; Rozziniet al., 2007; Talassi et al., 2007; Wenisch et al., 2007), while oth-ers only combined attention and memory training (Barnes et al.,2009; Clare et al., 2009; Greenaway et al., 2008). Some multifacetedprograms employed computerized cognitive training (Barnes et al.,2009; Rozzini et al., 2007; Talassi et al., 2007), which facilitatedthe individual approach but did not show increased improvementwhen compared to non-computerized training.

Cognitive training focusing on memory included the teaching ofcompensatory and restorative strategies including errorless learn-ing, errorful learning, spaced retrieval, visual imagery, face-nameassociations, mind mapping, cueing, categorization, hierarchicalorganization and method of loci. Many of these techniques wereapplied simultaneously (Belleville et al., 2006, 2011; Clare et al.,2009; Jean et al., 2010b; Kinsella et al., 2009; Kurz et al., 2009;Londos et al., 2008; Rapp et al., 2002; Troyer et al., 2008; Wenischet al., 2007), therefore, it is difficult to determine the isolated effectsof each method in the improvement of memory. Moreover, somestudies sought to investigate the effects of external memory aids

such as calendars and datebooks (Greenaway et al., 2008; Kinsellaet al., 2009; Londos et al., 2008) which indicated that individualswith A-MCI are able to learn internal strategies and benefit fromexternal memory aids.

1166 S.S. Simon et al. / Neuroscience and Biobehavioral Reviews 36 (2012) 11631178

Table 1Cognitive intervention and MCI: summary data.

Author (Year) N/Years of Education Design study/Format Treatment and control groups Duration follow-up

Belleville et al. (2011) Tx: 15 MCI Between group design Treatment group:15 NIYE: 13.7 (4.3)

Individual Psychoeducational informationand episodic memory training:learning of different mnemonicsand techniques to promoteelaborate encoding and retrieval.Functional MRI: during the twopre-training sessions and thepost-training session, patientsunderwent fMRI scanning wherethey did encoding and retrieval ofword lists

6 sessions (120 min)Once a weekNo follow-up

Hampstead et al. (2010) Tx: 6 MCI Non-controlled design Treatment group:YE: 15.7 (1.4) Individual Training in the use of explicit

memory strategies with face-namepairs. For each pair, they weretaught to visually identify a facialfeature, link a phonological cue tothat feature, and recall theassociated name. Functional MRI:during the pre-training and fifthpost-training session, patientsunderwent fMRI scanning as theyencoded the face-nameassociations

3 sessions (120 min)For 2 weeksNo follow-up

Banningh et al. (2010) Tx: 90 MCIC: 30 MCI

Between controlleddesign

Treatment group:

Educ. Level: 5.0 (1.1)Low = 1/High = 7

Group The programme combineselements from psychoeducation,cognitive-behavioral therapy andmemory rehabilitation (personalgoals, using of reminder cues,importance of making notes)


Control group:Waiting list

Jean et al. (2010a,b) Tx: 11 MCI RCT Treatment group:C: 11 MCIYE:14.4 (3.2)

Individual Cognitive training program:Psycho-educational sessions onmemory. Learning face-nameassociation using ErrorlessLearning and Spaced Retrievaltechniques

6 sessions (45 min)Once a week4 weeksFollow-up

Control group:Cognitive training program:Psycho-educational sessions onmemory. Learning face-nameassociation using an ErrorfulLearning

Barnes et al. (2009) Tx: 22 MCI RCT Treatment group:C: 25MCIYE: 16.8(3.2)

Group Computer-based cognitivetraining: exercises were design toimprove processing speed andaccuracy in the auditory cortex primary and working auditorymemory tasks

5 session per week(100 min each)For 6 weeksNo follow-up

Control group:Computer based activities:listening to audio books, readingonline newspapers and playing avisuospatially oriented computergame

Kinsella et al. (2009) Tx: 22 MCI RCT Treatment group:C: 22 MCIYE: 12.2 (4.5)

Group Memory Rehabilitation: Discussionabout memory functioning andtime to explore the variety ofexternal memory aid. Practice:several strategies for improvingorganization and memory. Familyparticipation

Once a week (90 min)For 5 weeks2 weeks/4 monthsFollow-up


S.S. Simon et al. / Neuroscience and Biobehavioral Reviews 36 (2012) 11631178 1167

Table 1 (Continued)


Clare et al. (2009) Tx: 1 MCI Single case Treatment group:Left school at 14 years old Individual Goal-oriented cognitive rehabilitation:

identifying and working on at least onepersonal rehabilitation goal relevant toeveryday lifeAttention training and exploring waysof coping with stress and anxiety(relaxation techniques). Introducingthe use of memory aid and strategiesfor learning new information andassociations, providing practice inthese using face-name associationsFunctional MRI: learning andrecognition of face-name associations

8 sessionsOnce a weekNo follow-up

Kurz et al. (2009) Tx: 18 MCI 10 MDC: 12 MCI

Between groupcontrolled design

Treatment group:

YE: 10.1 (1.9) Group Multi-component cognitiverehabilitation program: Practicalproblem-solving, self-assertivenesstraining, relaxation techniques, stressmanagement, cognitive trainingcomponents and motor exercisesOnce weekly the patients familymembers or other proxies were invitedto an information and support group

5 sessions per week (22 hper week)For 4 weeksNo Follow-up


Greenaway et al. (2008) Tx: 20 MCI Non-controlled design Treatment group:YE: 15.2 (2.5) Dyad

(Participant + Partner)Training on a calendar/note system(Memory Support System MMS):sessions provided orientation,modeling, practice use and homework.The MSS includes 3 sections: (a) eventsthat happen at a particular time appointments; (b) events that canhappen anytime daily to do items;and (c) a journaling section important events that happened thatday

12 sessions (60 min)For 6 weeks8 weeksFollow-up

Hampstead et al. (2008) Tx: 8 MCI Non-controlled design Treatment group:YE: 15.3 (1.8) Individual Training in the use of explicit memory

strategies with 45 face-name pairs. Foreach pair, they were taught to visuallyidentify a facial feature, link aphonological cue to that feature, andrecall the associated name

3 sessionsFor 2 weeks1 monthFollow-up

Troyer et al. (2008) Tx: 24 MCI RCT Treatment group:C: 24 MCIYE: 15.2 (3.3)

Group Presentation of information regardinga lifestyle factor that can affectmemory function. MemoryIntervention: focus on an everydaymemory problems memory forfuture events, memory for names andnumbers (spaced retrieval techniqueand semantic association) and memoryfor actions (one memory strategy wasto establish logical locations for itemsand to use them consistently andanother strategy focus on increasingattention)

10 sessions(120 min)Over 6 months3 monthsFollow-up


Londos et al. (2008) Tx: 15 MCI Non-controlled design Treatment group:YE: Group Educational presentation of the brain

and memory, and factors that caninfluence memoryTraining of compensatory memorystrategy techniques such as cueing,method of loci, mind-mapping andmemory aids (calendar, cell phonefunctions code cues, timer, etc.)

2 sessions per week(150 min each)For 8 weeks6 monthsFollow-up


Table 1 (Continued)


Jean et al. (2007) Tx: 2 MCI Case report Treatment group:(1) YE: 6 years(2) YE: 12years

Individual (1) Case 1 and Case 2 (1st intervention):Re-learn face-name associations of 5 famousindividual using Errorless Learning (EL) andSpaced Retrieval techniques(2) Case 2 (2nd intervention): Learn 10 newnames (first and last names) using EL and acontrol condition, the Errorful Learning (EF)paradigm

(1) 2 sessions (45 min each)Over 3 weeks(2) 2 weeks1/4/5 weeksFollow-up

Talassi et al. (2007) Tx: 30 MCI 24 MDC: 7 MCI 5 MD


Treatment group:

YE: 7.8 (4.5) Individual Cognitive rehabilitation program:Computerized cognitive training,occupational therapy and behavioraltraining

4 sessions per week(30 min each)For 3 weeksNo follow-up

Control group:Physical rehabilitation, occupational therapyand behavioral training

Rozzini et al. (2007) Tx1: 15 MCI RCT Treatment group 1:Tx2: 22 MCIC: 22 MCIYE:

Individual Cognitive computer based trainingMultidimensional software covereddifferent cognitive functions (e.g., memory,reasoning and visuospatial abilities) andcholinesterase inhibitors treatment

5 sessions per week(60 min each)For 4 weeks3 blocks of 20 by a break of2 months 3 monthsFollow-up

Treatment group 2:Cholinesterase inhibitors treatmentControl group 2:No treatment

Unverzagt et al. (2007) Tx: 193 MCI RCT Treatment group 1:C: 2773 NIYE: 13.5 (2.7)

Group Memory Training: Focus on verbal episodicmemory (training strategies)

10 sessions (6075 min)Over 56 weeks

Treatment group 2:Reasoning Training: Focus on improving theability to solve problemsTreatment group 3:Speed Training: Focus on visual search andthe ability to process increasingly moreinformation

Booster sessions: (4session75 min)Over 3 weeks (11 monthslater)1 and 2 yearsFollow-up

Control group:No treatment

Wenisch et al. (2007) Tx: 12 MCI 12 NI Between group design Treatment group:YE: 14.0 (2.4) Group Participants were given information about

memory functioningCognitive Stimulation: Words of welcome,reality orientation techniques newspaperreview, cognitive exercises (memory,executive function, visuo-spatial abilities) bymeans of an applied cognitive strategy,conclusion and strategy recall


Akhtar et al. (2006) Tx: 16 MCI 16 NI Between group design Treatment group:YE: Individual The participants were instructed that they

would be learning two lists of 10 words inerrorless and errorful learning conditions

1 session (4060 min)No follow-up

Belleville et al. (2006) Tx: 20 MCI 9 NIC: 8 MCI 8 NI


Treatment group:

YE: 14.6 (5.0) Group Participants were given information aboutcognitive changes observed in normal agingCognitive Stimulation: computer-assistedattention training and teaching differentmethods and strategies to improve memoryperformance



Rapp et al. (2002) Tx: 09 MCI RCT Treatment group:C: 10 MCIYE: >12 years (74%)

Group Education on memory, relaxation skillstraining; mnemonic strategies and cognitiverestructuring to change beliefs aboutmemory control

6 sessions (120 min)Once a week6 monthsFollow-up

Control group:No treatment

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On the other hand, some studies investigated whether indi-iduals with A-MCI are able to learn specific information usingingle techniques. Consistent evidence has shown that individualsearn better with errorless rather than errorful learning tech-iques (Akhtar et al., 2006; Jean et al., 2007), as has already beenbserved in individuals with AD (Clare et al., 2000). Moreover,his finding also occurred when errorless learning was associ-ted with the spaced retrieval technique (Jean et al., 2010b).nother study showed that visual and verbal cues, such as imagerynd nicknames, contributed to the patients ability to associateaces and names. These enhanced abilities were accompanied byhanges in the patterns of brain activation analyzed through fMRIn the medial frontal and parietal lobes, as well in the areaseighboring the temporalparietal junction (Hampstead et al.,010).Moreover, two other studies focused on the attainment of goals

irectly relevant to participants (Kinsella et al., 2009; Troyer et al.,008), and one study showed improvement in the functional andmotional spheres of patients using cognitive rehabilitation com-ined with cognitive behavioral therapy (Banningh et al., 2010).dditionally, psycho-educational aspects were also included in halff the studies, where information was provided to the participantsr to the relatives and caregivers concerning memory function andhe expected alterations caused by aging (Banningh et al., 2010;elleville et al., 2006, 2011; Jean et al., 2010b; Kinsella et al., 2009;ondos et al., 2008; Rapp et al., 2002; Troyer et al., 2008; Wenischt al., 2007).

.2. Can cognitive intervention effects be generalized to objectiveognitive measurements?

The cognitive measurements used before and after the interven-ions are described in Table 2. Some studies reported significantesults after cognitive interventions, especially when such mea-ures were directly related to aspects targeted during the programAkhtar et al., 2006; Belleville et al., 2006, 2011; Greenawayt al., 2008; Hampstead et al., 2008, 2010; Jean et al., 2010b;insella et al., 2009; Troyer et al., 2008). Nevertheless, many ofhese cognitive measures did not consist of standardized testsut rather assessed features specifically related to the trainingtself, such as reaction time and recognition accuracy (Hampsteadt al., 2008, 2010), number of remembered words (Akhtar et al.,006), memory of names and faces (Belleville et al., 2006; Troyert al., 2008; Hampstead et al., 2008, 2010) and compliance withhe use of a calendar system after training (Greenaway et al.,008).Whereas many studies had poor or insignificant results in the

bjective measurements of memory, others reported significantifferences with the same instrument. One example is the River-ead Behavioral Memory Test (RBMT), which could not identifyignificant changes in several studies (Clare et al., 2009; Jean et al.,007, 2010b; Talassi et al., 2007; Unverzagt et al., 2007). However,

randomized controlled trial involving the teaching of compen-atory memory strategies found significant changes in the itemreminding and envelope tasks after intervention (Kinsella et al.,009). This finding suggests that it is important to analyze the eval-ated items in each test separately to relate each task with theargeted aspect.

Other authors described a generalization of the training effectsn memory scores, such as the Rey-Osterreith Complex Figure TestROCF) recall (Talassi et al., 2007), word lists (Belleville et al., 2006,011; Kurz et al., 2009; Rapp et al., 2002) and Logical Memory

Wenisch et al., 2007). Together with these results, the effects ofnterventions showed little generalization towards the remain-ng cognitive spheres, however, generalized training effects werebserved in two programs using scores of executive (ROFT-copy)vioral Reviews 36 (2012) 11631178 1169

(Kurz et al., 2009; Talassi et al., 2007) and attention (Spatial Span)(Barnes et al., 2009) functions. It is worth emphasizing that, asa rule, computerized cognitive training showed low generaliza-tion of the trained aspects when assessed by cognitive testing,although it is also important to consider the relationship betweenthe aspects trained with the computer and the tests used for eval-uation.

The lack of sensitivity in some instruments, as well as themethodological limitations of studies, such as small sample sizes(Barnes et al., 2009; Belleville et al., 2006; Clare et al., 2009;Greenaway et al., 2008; Jean et al., 2007; Londos et al., 2008; Rappet al., 2002; Wenisch et al., 2007) and non-controlled clinical design(Clare et al., 2009; Greenaway et al., 2008; Jean et al., 2007; Londoset al., 2008; Wenisch et al., 2007), might have also contributed to thelack of significant findings in some of the cognitive measurementsassessed in these reports.

3.3. Can cognitive interventions improve subjectivemeasurements?

Subjective memory measurements assessing the perceptionof individuals regarding their own memory capabilities wereemployed in six studies, and all showed significant results. Inthis way, after cognitive interventions, individuals with A-MCIimproved the perception and control of their own memory abil-ities (Belleville et al., 2006; Jean et al., 2010b; Rapp et al., 2002),perceived improvements in learning after errorless learning train-ing (Akhtar et al., 2006) and, in two studies, increased the frequencyof memory strategy usage (Kinsella et al., 2009; Troyer et al.,2008).

Almost half the studies investigated the effects of interven-tions on mood (Banningh et al., 2010; Clare et al., 2009; Kurzet al., 2009; Londos et al., 2008; Rapp et al., 2002; Rozzini et al.,2007; Talassi et al., 2007; Wenisch et al., 2007). Although somestudies observed improvement, especially of symptoms of depres-sion, only three, including one that combined cognitive trainingand I-ChE treatment (Rozzini et al., 2007), described statisticallysignificant changes in scores of depression and anxiety, such asthe Beck Depression Inventory (BDI) (Kurz et al., 2009), GeriatricDepression Scale (GDS) (Rozzini et al., 2007; Talassi et al., 2007),and State and Trait Anxiety Inventory (STAI) Y1 and Y2 (Talassiet al., 2007). Regarding functional changes, few studies reportedimprovements in the scores of daily life activities as measured bythe Basic Activities of Daily Living (BADL) (Kurz et al., 2009; Rozziniet al., 2007), while others found no changes using the same assess-ment (Talassi et al., 2007). A possible reason for this inconsistencyis that individuals with A-MCI exhibit subtler difficulties in scoresmeasuring functioning in daily life activities, which makes it moredifficult to evaluate such alterations with instruments not specifi-cally designed for this purpose.

Two programs reported success in performing goal-orientedrehabilitation, showing functional improvement in goal-attainment and Canadian Occupational Performance Measure(COPM) (Clare et al., 2009; Londos et al., 2008), and one of thesestudies also reported significant changes in the quality of life(Quality of Life Alzheimers Disease QoLAD) and well being (WellBeing Scale) (Belleville et al., 2006).

Regarding the emotional sphere, one study showed that patientsbetter accepted their conditions (Illness Cognition Questionnaire acceptable) and, thus, were able to more effectively deal withan uncertain future when cognitive rehabilitation was combined

with cognitive behavioral therapy (Banningh et al., 2010). Otherevaluated aspects that did not show significant changes includedparticipants self-esteem (Jean et al., 2010b) and caregivers stress(Greenaway et al., 2008).


Table 2Measures and results: summary data.

Author (Year) Design study Measures (pre- and post-intervention) Baseline End ofintervention

Baseline Follow-up(FU)

Belleville et al. (2011) Between group design CNCMB No FUTrained versusuntrained stimuli

Word lists immediate recall p = EF)Ability p < 0.001 (EL + SR > EF) p < 0.001 (EL + SR > EF)Strategy ns ns

RBTM ns nsMMSE ns nsCVLT-II n/a nsDRS-2 n/a nsSES n/a ns

Barnes et al. (2009) RCT CTMT (D-KEFS) ns No FUComparison betweentreatments

Design fluency (D-KEFS) nsSpatial span p = 0.003RBANS ns

Total nsAttention nsImmediate memory nsDelayed memory p = 0.07Language nsVisuospatial p = 0.08 in favor of the

control groupKinsella et al. (2009) RCT CVLT-II ns

MCI treated versus nottreated

COWAT nsBNT nsProspective memory performanceRBMT Reminding/Envelop tasks p = 0.20 (group effect) Tx performed

significantly betterStrategy knowledge

Participant p = 0.047 (group effect) Tx performedsignificantly better

Family member p = 0.006 (group effect) Tx performedsignificantly better

MMQContentement ns nsAbility ns nsStrategy p = 0.024 Tx performed

significantly better at 2weeks but dissipated at4 months FU

Clare et al. (2009) Single case RBMT ns No FUStandardized profile score nsScreening score

Associative learning fMRI scan ns (Pre Int: 72.2%/PostInt: 97.2%)(Face name learning score)

Control task score nsPost-scan recognition task ns


Table 2 (Continued)



COPMPerformance nsSatisfaction with performance ns

HADSDepression nsAnxiety ns

Goals Fully achievedGoal 1 Partially achievedGoal 2

Kurz et al. (2009) Between group controlleddesign

CVLT delayed free recall p > 0.001 No FU

MCI treated versus nottreated

RCFT delayed recall p > 0.001

BDI p > 0.001BADL p > 0.001

Greenaway et al. (2008) Non-controlled design Compliance p < 0.0001 Remained high (p valuenot provided)

DRS-2 n/a nsCaregiver Burden n/a nsROIL n/a nsE Cog n/a ns

Troyer et al. (2008) RCT Strategy toolbox (knowledge) p < 0.001 Tx > C p = 0.016 Tx > CTreated versus not treated Strategy use on memory tasks p = 0.049 Tx > C ns

Name, number and wordlist recall ns nsMMQ

Contentment ns nsAbility ns nsStrategy (use at home) p = 0.021 Tx > C p = 0.004 Tx > C

Impact rating scale ns nsLifestyle importance ns ns

Londos et al. (2008) Non-controlled design Digit span (WAIS III) ns nsSpatial span (WAIS-R) ns nsDigit symbol (WAIS-R) ns nsRCFT ns nsAQT

Color ns p = 0.052Form p = 0.054 p = 0.005Color-form ns p = 0.044

COPMOccupational performance p = 0.003 p = 0.002Satisfaction performance p = 0.002 p = 0.001

QoLADMemory p = 0.003 p = 0.011Mood ns nsSelf ns ns

Hampstead et al. (2008) Non-controlled design Recognition accuracy p < 0.0001 p = 0.0002Trained versus untrainedlist

Response latencies p = 0.03 p = 0.01 (significantlyslower)

Rozzini et al. (2007) RCT MMSE n/a I-CHEs + TNPComparison between twotreatments and control

Short story recall n/a ns

Tx0 = I-CHEs Semantic verbal fluency n/a p < 0.01 Tx1 > Tx and CTx1 = I-CHEs + TNP Letter verbal fluency n/a ns

Raven n/a nsRCFT copy n/a p < 0.02 Tx1 > Tx0 and CRCFT delayed recall n/a nsNPI n/a nsGDS n/a p < 0.016 Tx1 > Tx0 and

C

Unverzagt et al. (2007) RCT BADL n/a p < 0.02 Tx0 > Tx1 and CMemory score (HTLV, RAVLT, RBMT)immed recall

ns ns1 ns2

Treated versus not treatedMCI 1 (1) and 2-year FU (2)

Reasoning score (Letter series Lettersets, Word series)

ns ns1 ns2

Speed score (UFOV) p < 0.001 ns1 p < 0.052


Table 2 (Continued)



Talassi et al. (2007) Between controlled design MMSE ns No FUComparison betweentreatments

Digit span forward ns

Digit span backward nsDigit symbol nsPhonemic fluency nsVerbal fluency nsVisual search nsRBMT immed recall nsRBMT delayed recall nsRCFT copy p = 0.05RCFT delayed recall p = 0.033Clock-drawing test nsGDS p = 0.012PPT p = 0.003Stai-Y1 p = 0.030Stai-Y2 p = 0.000BADL nsIADL ns

Jean et al. (2007) Case report (N = 2)(1): Participant 1 Face name association (1) (1): = (FU1)/ (FU2)(2): Participant 2 (2) EL > EF (2): (FU1)/n/aComparison betweentechniques (EL EF)

MMSE n/a (1): = (FU1)/ (FU2)

RMBT (profile score) n/a (2): = (FU1)/n/a(1): = (FU1)/ (FU2)(2): = (FU1)/n/a

Akhtar et al. (2006) Between group design Total words recall p < 0.05 (EL> EF) No FUComparison betweentechniques (EL EF)

Words recall across trails (learning) p < 0.05 (EL > EF)

Judgements of Learning (JOLs) p < 0.001 (EL > EF)

Wenisch et al. (2007) Between group design LM (WMS-R) No FUMCI Normal Immediate recall p < 0.05

Delayed recall p < 0.05WP (WMS-R)

Immediate recall nsDelayed recall ns

Verbal fluencyLetters nsCategory ns

TMT B nsGoldberg scale

Anxiety score nsDepression score ns

Belleville et al. (2006) Between controlled groupdesign

Face-name recall p < 0.01 No FU

MCI treated CNCMBList memory immediate p < 0.001List memory delayed p < 0.001

Memo-textMicro structure immediate nsMicro structure delayed p < 0.001Macro structure immediate nsMacro structure delayed nsVerbal fluency nsBrownPetersen (computer.) ns

QAMGeneral p < 0.05Personal events nsWell being scale p < 0.05


Table 2 (Continued)



Rapp et al. (2002) RCT Word list immediate ns NsMCI treated versus nottreated

Word list delayed ns p < 0.07 (Tx)

Grocery list immediate ns nsGrocery list delayed ns nsNames and faces immediate ns nsNames and faces delayed ns nsParagraph recall immediate ns nsParagraph recall delayed ns nsMFQ

Frequency of forgetting ns nsRetrospective functioning ns nsSeriousness ns nsMnemonic use ns p = 0.008 (C > Tx)

Memory controllability Inv.Present ability p = 0.008 (Tx > C) p = 0.05 (Tx > C)Potential improvement p = 0.005 (Tx > C) nsInevitable decline p < 0.07 (Tx) nsEffort utility ns nsProfile of mood and states Data not provided

Abbreviations: AQT, A Quick Test; BADL, Basic Activities of Daily Living; BDI, Beck Depression Inventory; BNT, Boston Naming Test; CNCMB, Cte-des-Neiges ComputerizedMemory Battery; Computer., computerized; COPM, Canadian Occupational Performance Measure; I-CHEs, cholinesterase inhibitors; COWAT, Controlled Oral Word AssociationTest; CTMT, California Trail Making Test; CVLT, California Verbal Learning Test; C, control group; D-KEFS, Delis-Kaplan Executive Function Scale; DRS-2, Dementia Rating Scale;E-Cog, Every Day Cognition; EF, errorful; EL, errorless; fMRI, Functional Magnetic Resonance Imaging; FU1, 1st follow-up; FU2, 2nd follow-up; GDS, Geriatric Depression Scale;HADS, Hospital Anxiety and Depression Scale; HVLT, Hopkins Verbal Learning Test; IADL, Instrumental Activities of Daily Living; ICQ, Illness Cognition Questionnaire; Immed,Immediate; Inv, Inventory; LM, Logical Memory; MCI, Mild Cognitive Impairment; MFQ, Memory Functioning Questionnaire; MMQ, Multifactorial Memory Questionnaire;MMSE, Mini-Mental State Examination; NPI, Neuropsychiatric Inventory; NI, Normal Individuals; ns, non significant; n/a, not applied; PPT, Physical Performance Test; QAM,Questionnaire dauto-valuation de la mmoire; QoLAD, Quality of Life in Alzheimers Disease; RANS-36, Item Health Survey 1.0; RAVLT, Rey Auditory Verbal Learning Test;RBANS, Repeatable Battery for Assessment of Cognitive Status; RBMT, Rivermead Behavioral Memory Test; RCFT, Rey-Osterreith Complex Figure Test; RCT, Randomized,Controlled Trial; ROIL, Record of Independent Living; SES, Self-Esteem Scale; SR, Spaced Retrieval; STAI, State and Trait Anxiety Inventory; TMT, Trail Making Test; TNP,N IS-III, WR ning;

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euroPsychological Training; Tx, treatment group; UFOV, Useful Field of View; WAevised; WMS-R, Weschler Memory Scale Revised; WP, Word Paired Associate Lear

.4. Can the benefits of cognitive interventions be maintaineduring the follow-up period?

To verify whether the effects of cognitive interventions coulde maintained over time, some researchers performed evaluationsfter follow-up periods varying from one week to two years. Someandomized and controlled trials that included follow-up evalu-tions focused on the teaching of internal strategies to improveemory and reported that some benefits persisted. In this way,

mprovement in the delayed recall of a list of words and the use ofearned strategies were reported as still present six months later;owever, there was a decrease in the control over the patientswn memory (Rapp et al., 2002). Although one study showed thathe use of internal strategies continued two weeks later (Kinsellat al., 2009), it was not maintained after three (Troyer et al., 2008)nd four (Kinsella et al., 2009) months. On the other hand, in a pilottudy where goal-oriented cognitive rehabilitation was carried out,enefits concerning satisfaction with self-performance and qualityf life remained 6 months later (Londos et al., 2008).In a randomized controlled trial with multifaceted computer-

zed cognitive training combined with the use of I-ChEs, the authorseported that after three months, there were improvements in cog-itive measurements, mood (depression) and functional scores.evertheless, in this study, follow-up measurements were onlyompared with those of the baseline because no evaluations wereompleted after the intervention (Rozzini et al., 2007).

In studies where specific abilities were trained, some benefitsere also maintained after training. A case study showed that theenefits of name-face association training were observed after oneeek but not after one month (Jean et al., 2007). On the other

and, the same author reported in a randomized, controlled studyhat after one month, participants were able to remember face-ame associations and sustained the perception of improvementf their memory abilities (Jean et al., 2010b). Additionally, a piloteschler Adult Intelligence Scale 3rd Edition; WAIS-R, Weschler Adult Intelligence YE, Years of Education; , amelioration; , deterioration; = no change.

study reported benefits of face-name association training after onemonth, as the participants were able to recognize the training mate-rial faster and with fewer errors than at the baseline (Hampsteadet al., 2008). Moreover, in a randomized, controlled trial, it wasreported that the benefits of speed processing training were pre-served after two years with booster sessions over the course of 11months (Unverzagt et al., 2007).

Despite the heterogeneity of the studies evaluated here, mostresults indicate that the benefits observed after interventions weresustained over time both in the objective and subjective measure-ments of memory, which suggests that individuals with A-MCI areable to maintain what they learn even after the intervention periodends. This effect is possibly strengthened by periodic booster ses-sions.

3.5. Can fMRI identify the effects of cognitive interventions inA-MCI patients?

Currently, only three studies have investigated the neuronal sys-tems underlying the effects of memory training in individuals withA-MCI by comparing the patterns of brain activation through fMRIbefore and after cognitive intervention. Although these studiesshowed differences among the type of training and fMRI paradigmemployed, they all found changes in brain activation associatedwith training, even in areas involving memory, as described inTable 3.

In a recent study, 15 A-MCI patients and 15 healthy elderlyparticipants were subjected to learning and training of memorystrategies (Belleville et al., 2011). During fMRI analysis, participantswere asked to memorize word lists (encoding) and recognize previ-

ously studied words among a list of new words (retrieval). Increasesin brain activation after training were found in the frontal, temporaland occipital areas. A-MCI patients recruited new and alternativeareas during the pre and post-training, however the right inferior


Table 3Functional MRI brain activation after explicit memory training.

Author (Year) Regions encoding Regions retrieval(recognition)

Belleville et al. (2011) Superior temporal gyrus Left Post-central gyrus Left Insula Inferior parietal

lobuleLeft

Thalamus Left Precuneus Left Putamen Middle frontal gyrus Left Globus pallidus Posterior cingulated Left/Right Inferior parietal lobule Right Superior temporal

gyrusLeft/Right

Superior frontal gyrus Right Insula Right Cerebellum Right

Hampstead et al. (2010) Medial frontal cortex (frontopola gyrus, rostralanterior, cinculate cortex)

Post-scan

Medial parietal cortex (posterior cingulate cortexand precuneus) Medial occipital cortex (infracalcarine andsupracalcarine, lingual gyrus) Frontal operculum Left Temporoparietal junction (angular gyrus;posterior superior temporal sulcus)

Left

Temporal cortex (middle and inferior temporalgyrus)

Left

Clare et al. (2009) Inferior frontal gyrus Left Inferior frontal gyrus Right Middle frontal gyrus Left Temporo-parietal Right

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arietal lobe was activated only after training, indicating that itsecruitment was necessary to improve these subjects performance.

In a pilot study of six individuals with A-MCI, significantncreases in brain activation after cognitive training were alsobserved; moreover, increases in the connectivity of areas relatedo explicit memory were reported (Hampstead et al., 2010). Par-icipants were subjected to name-face association training andhen asked to perform this kind of association during fMRI (encod-ng). The results showed an increase in the activation of a largerea of the cortex involving the following regions: medial partsf the frontal, parietal and occipital lobes areas neighboring theemporalparietal junction, left frontal operculum and some areasf the left temporal cortex. Furthermore, the increase in connectiv-ty after training mostly involved the medial temporal gyrus andoci in the occipital and precuneus cortices.

A separate case report described improvement in name-facessociation after cognitive training (Clare et al., 2009) with diminu-ion of brain activation in sensorial areas such as the upper visualreas (fusiform gyrus) and significant increases in the prefrontalesources relevant to memory (left inferior and middle frontal gyrusnd right inferior frontal gyrus). Furthermore, greater involvementf the temporalparietal junction was observed, which seems toe associated with the attention resources needed to retrieve cueselevant to memory (Cabeza et al., 2008).

Despite the methodological limitations of studies such as smallample sizes and lack of control groups, fMRI is able to detecthanges in brain activation related to cognitive training, suggest-ng that individuals with A-MCI exhibit high plasticity, which can besed as a tool to understand the effects of cognitive interventions.

. Discussion

Twenty studies were included in this review, and these suppliedome evidence that individuals with A-MCI benefit from cogni-

ive interventions because they are able to learn new informationsing different strategies, such as visual imagery, errorless learningnd spaced retrieval as well as external aids, including the use ofalendars. Moreover, some positive effects on daily life activities,junctionRightRight

the self-perception of patients regarding their own memory, mood(especially symptoms of depression), emotional features and qual-ity of life have also been described. These effects had variabledurations, although most lasted some months after interventionand one study (Unverzagt et al., 2007) reported that the effectswere maintained 2 years following the interventions.

Although the combination of techniques makes it impossible todistinguish which methods had the strongest impact on the results,some combination studies showed significant results (Bellevilleet al., 2006; Kinsella et al., 2009; Londos et al., 2008; Wenisch et al.,2007). Studies that focused on the teaching of a single strategy(Akhtar et al., 2006; Greenaway et al., 2008), the joining of twotechniques (Jean et al., 2010b) or the learning of specific infor-mation (Hampstead et al., 2008) also exhibited significant results,demonstrating that it is possible to more specifically understandthe effects of these strategies and thus supply more consistentgrounds for choosing techniques that might be most effective inclinical practice.

In this way, an interesting path for future research could involveinvestigating the isolated effects of some compensatory strategiesthat were used in combination in this population in order to bet-ter identify the possible benefits attained by single techniques.Another approach could combine memory compensatory strate-gies with implicit learning procedures, such as errorless learningand spaced retrieval, to enable individuals with A-MCI to learn rele-vant specific information (e.g., names of people) (Scott and Spector,2010).

Furthermore, it is important to continue investigating the effectsof the use of internal and external strategies to establish the bestpaths for patients to adapt to external aids (e.g., calendars and date-books), thus increasing the odds that use will continue followingthe intervention. By the same token, goal-oriented rehabilitation,although currently seldom used in individuals with A-MCI, appearspromising and seems to have higher odds of success when per-

formed individually (Clare et al., 2009).

The results of computerized cognitive training showed low gen-eralization when objectively measured in A-MCI patients. Thisis not surprising because healthy individuals also showed low

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eneralization of computerized cognitive training for untrainedasks (Owen et al., 2010) and because there is little evidence con-erning the benefits of computerized memory training in patientsith mild dementia (Clare et al., 2003). It is worth noting that ineveloping countries such as Brazil, access to computers is still lim-ted and the aged population might have little familiarity with theseaterials.Additionally, the educational levels and occupations of patients

ust be considered when analyzing the effects of cognitive inter-entions because both factors have an impact on cognitive reserveSol-Padduls et al., 2009). Since 82% of the studies included inhis review studied participants with an average educational levelqual to or greater than 12 years, it is possible that the positiveesults found are somehow related to this aspect. Therefore, stud-es in individuals with lower levels of education also need to beerformed to investigate this hypothesis.Although group interventions did not show better results com-

ared to individual interventions in patients with A-MCI, they are aood choice due to better cost-benefit relationships, thus allowingnterventions to reach a larger number of patients. Moreover, it isell-known that social interaction is an important factor in com-ating cognitive decline in the elderly (Fratiglioni et al., 2004) andre recommended to MCI patients (Petersen, 2011). Furthermoreognitive training completed in small groups and short sessionsas already been proven to be more effective than individual train-ng in a healthy aged population (Verhaeghen et al., 1992). On thether hand, individual interventions take into account personaleeds and, thus, favor engagement and increase understanding ofhe effects of cognitive interventions in each individual. Furtheresearch could combine individual and group interventions, whichas not yet been tested in A-MCI patients.A critical point observed in this review is the discrepancy

etween the results of subjective and objective memory mea-urements, i.e., the self-perception of patients regarding themprovement of their own memory abilities did not always matchhe results of cognitive tests. This might have been due to the facthat the latter assessments were not directly related to the trainedspects. Some authors have reported that the problem with usingests originally designed to aid in diagnosis to measure rehabilita-ion is that these tests evaluate multiple cognitive abilities insteadf a single cognitive construct. Moreover, they may lead to falseonclusions about the relevance of results concerning individualaily function (Johnstone and Stonnington, 2001).Thus, the results of the reviewed studies indicate that the bene-

ts of interventions are more significant when the evaluated tasksre directly related to the particular corresponding intervention,uggesting a limited level of generalization of the effects obtained,hich might be associated with both the suitability of the chosen

nstruments and the methodological limitations observed in sometudies, such as small sample size and lack of control groups.

An alternative method for understanding the effect of cogni-ive interventions is to employ functional neuroimaging beforend after the intervention. Monitoring of A-MCI patients by fMRIndicated that there are changes in the pattern of brain activa-ion directly related to memory training (Belleville et al., 2011;lare et al., 2009; Hampstead et al., 2010) with increases in acti-ation of several areas of the brain, including the frontal, temporalnd occipital lobes, as well as an increase in the connectivityf areas related to explicit memory, such as the medial tem-oral gyrus and the precuneus (Hampstead et al., 2010). Thesendings agree with models for brain compensation in aging anduggest that the maintenance of memory function is related to

he activation of specialized areas and recruitment of new brainegions (Cabeza, 2002; Reuter-Lorenz, 2002; Stern et al., 2005),hus helping to map out some of the brain pathways associatedith brain plasticity in A-MCI patients. Nevertheless, additionalvioral Reviews 36 (2012) 11631178 1175

studies, in particular controlled clinical trials in individuals withA-MCI and AD, are still needed to understand the neurobiologi-cal effects underlying cognitive interventions (Van Paasschen et al.,2009).

Due to the controversy surrounding the use of I-ChE in indi-viduals with A-MCI, only one study combined this treatment withcognitive interventions, and therefore, the benefits of the combineduse of pharmacological and non-pharmacological interventionsmust be further studied in this population. Moreover, this datais important because these interventions combined can stabilizeor even improve cognitive and functional performance of patientswith mild AD (Bottino et al., 2005).

Several studies have indicated that physical activities in indi-viduals with MCI have benefits on cognition (Lautenschlager et al.,2010), such as in executive functions (Baker et al., 2010; Scherderet al., 2005), attention (van Uffelen et al., 2008) and memory (vanUffelen et al., 2008, 2009; Lautenschlager et al., 2008). Some authorsalso described long term benefits in cognition (Lautenschlager et al.,2008) and suggested that physical activity can delay the MCI onset(Geda et al., 2010) and reduce risk for developing AD (Scarmeaset al., 2009). However, only one of the studies reviewed includedthis aspect in a rehabilitation program, with significant improve-ment in memory tests, symptoms of depression and daily livingactivities (Kurz et al., 2009). Nevertheless the specific contribu-tion of the physical exercise to the results was not clear. Therefore,future research with MCI patients should compare the efficacy ofphysical activities programs with cognitive interventions as wellas evaluate further benefits on cognitive measures (subjective andobjective) of both interventions in combination.

Despite frequent advances in cognitive interventions, the iso-lated effects of psycho-educational interventions in A-MCI patientsand/or their relatives are not yet known. Nevertheless, these inter-ventions appear to increase adhesion to treatment and assistrelatives in dealing with the difficulties that arise during thefollow-up period of patients suffering from this condition. Onemeta-analysis reported that psycho-educational intervention inthe caregivers of patients with dementia improved knowledgeabout the disease and favored a reduction in caregiver psychologi-cal stress (Brodaty et al., 2003).

It is worth noting that studies do not always assess the impact ofcognitive interventions on daily life activities, possibly because thecognitive difficulties of A-MCI, by definition, have discrete impactson daily functioning. However, some authors suggest that complexdaily life activities are already affected in individuals with MCIand that it is possible to measure them (Farias et al., 2006). Wemay speculate that memory interventions must have an impact onsuch abilities (Greenaway et al., 2008), and thus it is important toevaluate them in future studies of patients with MCI.

Moreover, a limitation of the reviewed studies is the hetero-geneity of the MCI groups. First, the studies did not provide dataabout longitudinal characteristics of the MCI subjects, for exam-ple, if they can be considered stable MCI over time or are revertingto normal cognition. Second, many studies did not differ betweenA-MCI single and multiple domains on methods and no one ana-lyzed separately the results regarding the A-MCI subtypes. Thus,the question if these conditions would respond differently to thecognitive interventions remains. We believe these methodologi-cal limitations contributed to the varying results of the studies.Future researches should make clear the MCI subtypes includedin the study as well as analyze separately the results of each MCIsubtype.

On the article describing the new criteria recommendations

for MCI (Albert et al., 2011) the authors postulated that biomark-ers for both beta-amyloid protein (Ab) and neuronal injury couldbe useful to differentiate MCI due to AD and MCI (unlikelydue to AD), which would be important to understand the decline

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haracteristics of these groups and planning adequate inter-entions to each condition. Also, biomarkers studies reportedifferences between MCI converters and stable subjects ana-yzed retrospectively (Hampel et al., 2010). By this perspective, it isossible to speculate that biomarkers could be useful to differenti-te between MCI patients who may have greater effects of cognitiventerventions or not; however, other aspect need to be considered,uch as cognitive reserve factors (Stern, 2002).

For example, the interaction between educational level andiomarkers measures can be useful to distinguish MCI profiles (sta-le or converter), which can help to differentiate between MCIatients who may respond better to cognitive interventions. Aecent study reported that stable MCI patients were better edu-ated, performed better cognitively, had higher Abeta42 levels andower levels of t-tau. On the other hand, converting MCI patientsith higher education had lower levels of Abeta42 and performedqually in neuropsychological tests compared to those with lowerducation (Rolstad et al., 2009). These results are consistent withhe cognitive reserve theory and suggest that cognitive reserveay be protective against amyloid related cognitive impairment

Dumurgier et al., 2010) as well as against tauopathy (Rolstad et al.,010). Other authors described that the clinical severity is notlways related to biomarkers levels (Sol-Padulls et al., 2011),eporting that t-tau CSF concentrations were associated with grayatter atrophy in neuropathologically areas related to AD, whereas

he p-tau(181) association was largely dependent on the degree oflinical severity. They concluded that the relationship between CSF(142) and clinical severity seems to be modulated by cognitiveeserve, suggesting that there may be subjects with pathologicalevels of A(142) and high cognitive reserve who remain clinicallysymptomatic.In summary, we believe that there is a complex interaction

etween cognitive reserve factors (educational background, occu-ational attainment, premorbid intelligence quotient, leisure andognitively stimulating activities) and each biomarker of neuronalnjury and neurodegeneration, modulating the benefits from cog-itive interventions. Further studies are needed in order to analyzehe effects of cognitive interventions accordingly to MCI conditionsMCI stable or converter), which may have different biomarkersresentations.The results of the present review must be interpreted with

ome caution due to the methodological limitations of the stud-es discussed here, such as small sample size, non-controlledxperimental designs and heterogeneity of the instruments andechniques used. The lack of statistical power of some studies prob-bly contributed to non-significant results, and the small sampleizes might have been due to the difficulty in obtaining homoge-ous case series of individuals with A-MCI. At times, the cognitiveomplaints of A-MCI patients are not sufficient to cause patientso seek specialized assistance or else patients might not receivedequate attention from health-care professionals. Moreover, addi-ional data are needed regarding the persistence of benefits overime together with long-term follow up periods. Since A-MCI is aegenerative condition in some patients, it is crucial to assess theongitudinal progression of clinical findings.

. Conclusion

Cognitive interventions led to improvements in the globalognitive functioning, especially memory, of A-MCI patients,emonstrating that these individuals are able to learn new informa-

ion. Benefits have also been reported concerning meta-memory,ood (particularly symptoms of depression), emotional features,aily life activities and quality of life. In studies including follow-p assessments, the effects of interventions exhibited variablevioral Reviews 36 (2012) 11631178

permanence independently from the cognitive component evalu-ated or the duration of the follow-up period.

Investigation of the isolated effects of compensatory strategiesas well as the combined use of internal and external strategiesdeserves more attention in future studies. Goal-oriented rehabil-itation and the combination of individual and group interventionsseem to be promising fields for future research. Computerizedtraining, in spite of having shown low generalization with theinstruments employed, is an attractive tool, especially whencombined with the teaching of memory strategies. However, itsavailability is still probably limited in developing countries dueto patients limited access to the required technology. Moreover,in many developing countries, significant fractions of the elderlypopulation have low levels of education, which, when consider-ing cognitive reserve as a hypothetical factor favoring the efficacyof the intervention, may lead to findings different from the onesdiscussed in this review. For this reason, the impact of patient edu-cational background on cognitive interventions needs to be furtherinvestigated.

An important issue to consider in studies assessing the efficacyof cognitive intervention concerns the instruments of measure-ment. Both standardized tests and scales and specifically designedinstruments have advantages and disadvantages, and either maystrengthen the hypothesis concerning the lack of generalizationof benefits to the fact that they do not evaluate effects appropri-ately. Therefore, it is important to develop a consensus concerningthe methods applied in this kind of research. Subjective memoryscores seem to agree with the notion that interventions must causeimprovement in patients and must be perceived by them, thusassessing individual effects. Although only preliminary data havebeen reported, the use of functional neuroimaging before and aftercognitive interventions already points to changes in the pattern ofbrain activation associated with cognitive training, involving dif-ferent brain areas, including those areas associated with memory.These results suggest that functional neuroimaging might repre-sent a useful objective measurement to understand the effects ofcognitive interventions.

In the face of the promising results concerning cognitive inter-ventions and the lack of pharmacological treatment for individualsat a high risk of developing AD, it is essential to continue investigat-ing the effects of these non-pharmacological interventions throughcontrolled randomized trials in large samples and with long-termfollow-up of benefits and to test new ways of observing and mea-suring the benefits acquired through such treatments.

Acknowledgements

We wish to thank Dra. Candida Helena Pires de Camargo for herassistance with comments and suggestions.

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