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Neuropsychol Rev. Author manuscript; available in PMC 2017 September 08.
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Published in final edited form as:

Neuropsychol Rev. 2016 September ; 26(3): 225–251. doi:10.1007/s11065-016-9330-4.
Everyday Impact of Cognitive Interventions in Mild Cognitive

Impairment: a Systematic Review and Meta-Analysis
M. J. Chandler1, A. C. Parks1, M. Marsiske2, L. J. Rotblatt2, and G. E. Smith2
1Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA
2University of Florida, Gainesville, FL, USA
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Abstract
Cognitive interventions in Mild Cognitive Impairment (MCI) seek to ameliorate cognitive
symptoms in the condition. Cognitive interventions may or may not generalize beyond cognitive
outcomes to everyday life. This systematic review and meta-analysis sought to assess the effect of
cognitive interventions compared to a control group in MCI on generalizability outcome measures
[activities of daily living (ADLs), mood, quality of life (QOL), and metacognition] rather than
cognitive outcomes alone. PRISMA guidelines were followed. MEDLINE and PsychInfo were
utilized as data sources to locate references related to cognitive interventions in individuals with
MCI. The cognitive intervention study was required to have a control or alternative treatment
comparison group to be included. Thirty articles met criteria, including six computerized cognitive
interventions, 14 therapist-based interventions, and 10 multimodal (i.e., cognitive intervention plus
an additional intervention) studies. Small, but significant overall median effects were seen for
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ADLs (d = 0.23), mood (d = 0.16), and metacognitive outcomes (d = 0.30), but not for QOL (d =
0.10). Computerized studies appeared to benefit mood (depression, anxiety, and apathy) compared
to controls, while therapist-based interventions and multimodal interventions had more impact on
ADLs and metacognitive outcomes than control conditions. The results are encouraging that
cognitive interventions in MCI may impact everyday life, but considerably more research is
needed. The current review and meta-analysis is limited by our use of only PsychInfo and
MEDLINE databases, our inability to read full text non-English articles, and our reliance on only
published data to complete effect sizes.
Keywords
Mild Cognitive Impairment; Cognitive intervention; Activities of daily living; Quality of life;
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systematic review; meta-analysis
Introduction
Research into interventions for Mild Cognitive Impairment (MCI) has been growing
exponentially since the turn of the twenty-first century. The concept of MCI was formulated
almost 20 years ago now (Petersen et al. 1999; Smith et al. 1996) to help focus research and
Contact: M. J. Chandler, chandler.melanie@mayo.edu.

Chandler et al. Page 2
clinical practice on people at risk for but having not yet developed dementia. MCI is
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characterized by 1) a cognitive concern, 2) cognitive impairment on psychometric testing, 3)

largely intact activities of daily living (ADLs), and 4) not meeting criteria for dementia
(Albert et al. 2011). The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition
utilizes this concept of MCI in their diagnostic designation of Minor Neurocognitive
Disorder (American Psychiatric Association 2013). Frequently, the cognitive problems
experienced by individuals with MCI negatively impact their lives, including mood,
relationships, treatment compliance, and independence.
MCI was once viewed as a condition that was not conducive for rehabilitation because of its
likely progressive course to dementia. However, there has been increasing interest in
whether individuals with MCI can benefit from cognitive intervention and rehabilitation
techniques. A cognitive intervention is an intervention aimed to positively impact the
cognitive functioning of an individual. To further operationalize types of cognitive
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interventions, Linda Clare and her colleagues (2003) advocate distinguishing the concepts of
cognitive stimulation, cognitive training, and cognitive rehabilitation. Cognitive stimulation
usually refers to activities that are not aimed towards a systematic improvement of a
particular cognitive domain, but rather cognitive activity that is thought to be “stimulating”
and good for the brain in general. Cognitive training usually involves manualized training to
aid function in a particular cognitive domain, such as memory, language, or problem solving.
Cognitive rehabilitation usually refers to a more individualized approach based on goal
setting with the person and often their family member(s). Several early reviews into
cognitive interventions in MCI were published between 2008 and 2012, including a
Cochrane Review of published randomized controlled trials (RCT) through 2007 that found
little evidence for the benefit of cognitive interventions in MCI (Martin et al. 2011). Less
strict reviews (i.e., those not requiring RCTs at that early stage of the field) were more
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positive, noting hopeful outcomes on cognition, mood, and daily life after cognitive
rehabilitation (e.g., Tsolaki et al. 2011; Gates et al. 2011).
Repeatedly, these reviews pointed to a need for larger trials, randomized control groups, and
consistency in outcomes measured (Belleville 2008; Jean et al. 2010a; Stott and Spector
2011; Hampstead et al. 2014). The few reviews that set out to perform meta-analyses were
stymied by the wide variety of methods employed in the cognitive interventions and variable
outcomes measured (e.g., Gates et al. 2011; Kurz et al. 2011; Cooper et al. 2013). Li et al.
(2011) did perform a meta-analysis on studies containing either a cognitive or functional
outcome but not all of the studies were controlled trials (CTs). They found a moderate
impact on language (d = 0.51), episodic memory (0.45), anxiety (0.51), and functional
ability (0.55), but little effect on other areas of cognition, quality of life (QOL), or
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depression. They noted, as have others (Martin et al. 2011), that the effect sizes were smaller
in the controlled studies compared to the single arm studies.
Few reviews have looked at the everyday impact of cognitive interventions in MCI, and
some have even required a cognitive outcome measure for inclusion in the review (e.g.,
Reijnders et al. 2013). Lack of focus on real-world impact outcomes appears to be
particularly true in computer-based interventions (Lampit et al. 2014). While requiring a
cognitive outcome in a cognitive intervention trial may at first seem straight forward, the

underlying assumption is that cognitive interventions in MCI are meant to ameliorate decline
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or even restore cognitive ability. However, the goals of cognitive interventions or cognitive
rehabilitation are not exclusively meant to restore cognition. In rehabilitation, the focus can
be on impacting the ability itself by returning it to its baseline (restorative) or at least
improving it to some degree (remediation), or the focus can be on helping an individual
adapt to the changed ability without attempting to improve the ability itself (compensation).
Both can be addressed in rehabilitation simultaneously as well.
In the case of MCI due to a neurodegenerative condition, the pathological burden in the
brain by time of symptom onset is often substantial. Restoring innate memory or other
cognitive ability at this point may not be feasible. Rather, the goal may often be
compensation or adaptation to a lost ability, where no improvement in measured cognitive
ability is expected. Thus, while some reviews may find moderate to large effect sizes for
memory outcomes (e.g., Gates et al. 2011), it is not surprising that some reviews find little
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impact on standardized neuropsychological tests (e.g., Simon et al. 2012; Cooper et al.
2013).
Most recently, when performing a systematic review of all types of nonpharmacological

intervention in MCI (i.e., a mix of cognitive therapy interventions, physical exercise
programs, and psychotherapy interventions), Rodakowski and colleagues (2015) noted the
continued infrequence of source articles and reviews focused on everyday life impact and
not just cognitive outcome. Only 50 % of the studies in their review conducted through
November 2014 actually measured such impact. They found that remediation based
interventions appeared to have the largest impact on cognitive variables, and compensation
based interventions showed promise to have a larger impact on everyday functioning
variables. Despite this, most articles appear to continue to relegate these daily impact
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measures to “secondary outcomes” or “other treatment targets” behind the primary cognitive
outcomes. This is unfortunate, as individuals with MCI and their partners have been shown
to report quality of life and self-efficacy as the most important outcomes they want to see
addressed in cognitive intervention programs (Barrios et al. 2016).
Giebel and Challis (2015) searched the literature in May of 2013 and found only three
cognitive intervention studies in MCI that had an everyday functional ability outcome. These
authors noted that while these three studies were encouraging that cognitive training could
improve ADLs in MCI, the studies lacked clear descriptions of the interventions, apparent
non-standardized administration of the interventions, and weak theoretical rationale for
choice of cognitive strategy. This undermined the interpretability of the impact of cognitive
training on ADLs in MCI. Coyle et al. (2015) focused their systematic review on
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computerized interventions through January 2014 and found that eight of sixteen studies
looked at mood and ADLs as secondary outcomes, and five of sixteen looked at
metacognitive outcomes. Mood improvements were noted in a little under half of the
computerized interventions that assessed mood, but none of the eight studies that looked at
ADLs found change after the computerized intervention. This may be expected, as
computerized interventions are usually remediation based rather than compensation based,
and thus cognitive outcomes were more likely to show improvement.

The growth of cognitive intervention studies in MCI from the first published RCT in 2002
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(Rapp et al.) to the date of this review is show in Fig. 1. Given the significant growth of
research in this area, and the dearth of reviews targeting daily life outcomes after cognitive
intervention in MCI, we sought to determine if there had been a recent increase in the
utilization of everyday outcomes in cognitive intervention trials in MCI. We focused our
search on studies that compared everyday or “generalizability” outcomes in individuals with
MCI who had received a cognitive intervention contrasted to a comparison group. We
defined generalizability outcomes not as measured change in cognition, but rather the
impacts on daily life to which the cognitive interventions may generalize or transfer.
Specifically, this includes outcomes such as measures of ADLs, mood, QOL, or
metacognitive outcomes (how one feels/thinks about one’s cognitive process). We organized
these studies based upon what type of intervention was administered. Namely, studies were
presented in groups of computerized interventions (where the goal is most often cognitive
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restitution), therapist-based interventions (where the goal is most often cognitive

adaptation), and the emerging trend of multimodal interventions, where cognitive therapy is
combined with other nonpharmacological interventions, such as physical exercise and/or
psychotherapy (often with both cognitive restitution and adaptation goals).
Methods
Search Strategy
PRISMA guidelines were followed (Moher et al. 2009); however, the protocol was not
registered. Using the Ovid interface, an experienced librarian searched the MEDLINE and
PsychInfo databases based on the PICOS statement provided by the authors. Both searches
were completed on October 30, 2015 and included all possible publications up until that
date. There were no restrictions on language or publication date; however, the searches were
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limited to adult participants. Search strategy included MeSH and PsychInfo controlled
vocabulary terms and keywords, including Mild Cognitive Impairment, MCI, cognitive
therapy, and rehabilitation. The complete strategy can be found in the Appendix.
Inclusion and Exclusion of Publications

Two authors (MJC and GES) independently reviewed the list of potential articles produced
by the search strategy. Criteria for including or excluding articles were determined a priori.
Study participants had to be diagnosed with MCI (Petersen et al. 1999; Albert et al. 2011;
Winblad et al. 2004). Cognitive interventions could include cognitive stimulation, cognitive
training, or cognitive rehabilitation approaches (Clare et al. 2003). Articles were excluded in
the following order of priority: 1) participants were not MCI, 2) there was no cognitive
intervention, 3) the publication was a review rather than primary study, 4) the publication
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was not peer reviewed, 5) the sample included MCI, but was mixed with healthy elderly
and/or dementia subjects and independent analysis of the MCI group was not provided, 6)
the study was not a CT (either CTs or RCTs were acceptable), 7) there was no generalization
outcome (e.g., only objective cognitive testing outcome), 8) the sample was a duplicate of
another published paper without novel information (additional studies from the same sample
were included if they represented an additional follow up point or different outcome
variables), and 9) the status could not be determined because the article was not in English

(all had English abstracts and some could be excluded prior to this ninth criteria based upon
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that abstract).
Titles were first reviewed for obvious exclusions. If it was unclear whether the article should
be excluded after reading the abstract, the full text was reviewed. Authors MJC and GES
then compared their reviews of articles to ensure that the same studies had been excluded or
included in the order of priority listed above. No metric of inter-rater reliability was
assessed. Any discrepancies between the two authors were discussed, the full text articles
consulted as needed, and an agreement reached on how to best classify the article. The
application of these criteria assured that all studies included in this analysis were clinical
trials involving generalization outcomes from cognitive or multimodal interventions
delivered to exclusively MCI cohorts compared to a control/comparison group that were
presented in a peer reviewed English language publication.
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Extraction of Data from Articles

Articles to be included were divided into three subcategories: 1) computerized interventions,
2) therapist-based interventions, and 3) multimodal intervention articles, where a cognitive
intervention (either computerized or not) was given as well as some other non-
pharmacological intervention (e.g., physical exercise or psychotherapy). This method of
grouping articles was conceptually based, and for organizational purposes. Three authors
(MJC, GES, and ACP) independently extracted data from reading the full text articles to
complete a priori created data tables. Tables with extracted data and articles were then
reviewed by a second person for accuracy to ensure no errors. The data selected for
extraction can be found in the columns of Tables 1, 2, 3, 4, 5, and 6.
Meta-Analysis
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Meta-analysis was conducted (by MM and LJR) on all studies that included a comparison
group that allowed us to isolate the unique effect of a particular treatment (e.g., no contract
control, social contact control, or alternative treatment). Meta-analysis was restricted to
available data in published manuscripts. Data was extracted from the articles (LJR) to
calculate effect sizes for further use in the meta-analysis (MM). The variables utilized to
calculate effect sizes are presented in Tables 2, 4, and 6. To provide a conservative test of
effect, we used the most distal follow-up occasion available for each study; thus, if a study
had an immediate posttest and 6- and 12-month follow-ups, only the 12-month follow-up
was considered. For most studies, we quantified effect size as standardized mean difference
(Cohen’s d), using the formula:
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This approach quantified the metric of change in terms of the original variability of the
sample (so that a d = 1 would mean that the treatment group experienced one standard
deviation more improvement than control). For all studies, standardized mean differences
were coded so that positive values meant that the treatment group experienced more
improvement (i.e., in the desirable direction) than the controls.

Following the recommendations of Field and Gillett (2010) we used random effects models
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to assess the magnitude of effects; generally speaking, random effects permit the
generalization of findings beyond the specific sample of articles included in this study.
Heterogeneity was quantified both in terms of the Q statistic, and tau squared (Hedges and
Olkin 1985; Higgins and Thompson 2002; Higgins et al. 2003). To evaluate the effect of
categorical moderator variables (i.e., therapy modality and outcome type) on effect sizes, we
conducted a multiple regression via mixed model. The model assumed a general linear
model in which each effect size could be predicted from the moderator, which was coded via
dummy coded contrast weights, and which was estimated via generalized least squares
(Field 2003; Overton 1998).
We also attempted quantitative estimates of the extent to which effect size estimates might
show evidence of publication bias. Several methods were used to assess the magnitude of
estimated publication bias and its impact on meta-analysis findings. First, for each group of
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studies, we estimated Rosenthal’s (1979) Fail Safe N, which estimates the number of
unpublished studies that would need to exist to turn a significant population effect size
estimate into a non-significant one. Second, we employed the Begg and Mazumdar’s (1994)
rank correlation test for publication bias, which estimates Kendall’s tau between a
standardized form of the effect size and its associated variance; when the relationship is
strong/significant, this signifies publication bias (Field and Gillett 2010). However, since the
test lacks power for small meta-analyses, non-significant associations cannot be taken as
evidence for the absence of bias. Third, we employed a sensitivity analysis approach
described by Vevea and Woods (2005), which produces adjusted effect size estimates. This
approach specifies four typical weight functions to adjust effect sizes, which they label
“moderate one-tailed selection,” “severe one-tailed selection,” “moderate two-tailed
selection,” and “severe two-tailed selection.”
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Results
The initial search terms resulted in 463 articles for further review. Following the article
inclusion/exclusion process (Fig. 2), 30 articles remained for inclusion. Of these, six were
computerized interventions, 14 were therapist-based interventions, and 10 multimodal
studies. In the multimodal studies, cognitive outcomes compared to a control group could be
extracted from one additional computerized (Fiatarone Singh et al. 2014) and two additional
therapist-based interventions (Lam et al. 2015; Nakatsuka et al. 2015). Thus, aspects of these
studies appear in both analyses: the isolated cognitive intervention outcomes in the
respective computerized or therapist-based intervention sections, and the cognitive
intervention outcomes when combined with other nonpharmacological interventions in the
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multi-modal section.
Computerized Interventions Overview

We included six studies that involved computerized cognitive interventions and one
additional multimodal study in which results from a computerized intervention could be
extracted (seven total studies; see Tables 1 and 2). Only one (Talassi et al. 2007) of these
seven studies was not a RCT. In this study, method of group assignment was not specified,

but it is unlikely that randomization was used given the notably unbalanced group sizes.
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Sample sizes ranged from 8 to 51 (M = 21.3, SD = 15.2) and 7 to 49 (M = 17.7, SD = 14.7)

for the intervention group (IG) and the control groups (CG) respectively, based upon
numbers at final follow-up. One study (Fiatarone Singh et al. 2014) was a clear outlier with
the 51 and 49 participants in the IG and CG groups. Excluding that study, the mean across
studies for IG was 16.3 (SD = 8.5) and CG was 12.5 (SD = 5.6).
Recruitment rates were not routinely reported. For those studies utilizing some
approximation of CONSORT reporting guidelines (Schulz et al. 2010) recruitment rates
ranges from 4.5 % (Fiatarone Singh et al. 2014; Hughes et al. 2014) for community samples
to 33 % (Gagnon and Belleville 2012) for a clinical sample (M = 37.8; SD = 36.8). Pooled
(intervention and control) retention rates ranged from 64 % (Maurice Finn and McDonald
2011) to 100 % (Hughes et al.; M = 86.3; SD = 35.1).
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Sessions lasted from two weeks (Gagnon and Belleville 2012) to nine months (Rozzini et al.
2007), with a median of 25.5 h of intervention (range: 6–130). For four of seven studies, the
last follow-up was end-of-treatment. Three studies (Fiatarone Singh et al. 2014; Gaitan et al.
2013; Hughes et al. 2014) ended treatment after 12 to 26 weeks but conducted delayed
follow-ups at 12 to18 months. The longest follow-up period reported was 18 months
(Fiatarone Singh et al. 2014).
Group intervention was used in three studies while individual interventions were provided in
four studies. Training programs targeting multiple cognitive domains were used in five of
seven studies. Focused attention training was used in Gagnon and Belleville’s (2012) study.
Hughes et al. (2014) used a computer gaming intervention (Wii video games) that required
not only attention but also movement.
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Therapist-Based Interventions Overview

Of the 14 articles included, two represented the separate publications of treatment-end
outcome (Buschert et al. 2011) and then longer-term follow up in the same sample (Buschert
et al. 2012). Cognitive intervention only outcomes could be determined in one multi-modal,
non-computer intervention (Lam et al. 2015). Thus, there are 14 studies presented in Tables
3 and 4. Of these, all were RCTs with the exception of one which was a CT (Belleville et al.
2006). Sample sizes ranged from seven to 145 for the intervention group (M = 27.5, SD =
35.3) and 4 to 131 (M = 26.9, SD = 33.2) for the control groups (based upon numbers at last
follow-up). One study (Lam et al. 2015) was a clear outlier with 145 and 131 participants in
the IG and CG groups. Excluding that study, the mean across studies for IG was 19.1 (SD =
7.2) and CG was 18.9 (SD = 9.1). Recruitment rates ranged from 36.0 to 91.3 % (M = 68.4,
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SD = 19.6). Attrition rates averaged 17.7 % (SD = 7.4), for a total retained sample size
ranging from 65.2 to 90.9 %.
Sessions lasted from three weeks (Jean et al. 2010b) to 12 months (Lam et al. 2015). Hours
of contact could be calculated in 12 of the 14 studies (excludes Finn and McDonald 2015;
Rojas et al. 2013), ranging from 4.5 (Jean et al. 2010b) to 156 h (Lam et al. 2015).
Excluding Lam et al. as an outlier, studies averaged 15.5 h of intervention (SD = 10.1).
Participants were followed through training end in six of the 14 studies, and often the

waitlist control group was then allowed to participate in the intervention (Belleville et al.
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2006; Brum et al. 2009; Kinsella et al. 2009; Konsztowicz et al. 2013; Troyer et al. 2008).
The longest follow-up period reported was 28 months (Buschert et al. 2012).
The majority of the therapist-based intervention studies (11/14) utilized a group setting for
their intervention, only three studies (Finn and McDonald 2015; Greenaway et al. 2013; Jean
et al. 2010b) had solely individual sessions. Nakatsuka et al. (2015) had both group and in-
home individual sessions. In terms of the therapy content, two studies focused exclusively
on one specific type of learning strategy: repetition lag training (Finn and McDonald 2015)
or errorless learning (Jean et al. 2010b). One study focused exclusively on training of an
external memory (calendar) aid (Greenaway et al. 2013). Konsztowicz et al. (2013)
contrasted a mnemonic memory training group, external aid calendar group, and a waitlist
control. All the remaining studies (10/14) had a multicomponent “memory training” group
that typically consisted of education about memory and memory loss, cognitive exercises,
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mnemonic training, as well as encouragement to use external aids without detailed training.
Multimodal Interventions Overview

Ten studies involving multimodal interventions were reviewed involving multimodal
interventions (i.e., cognitive intervention plus another non-pharmacological intervention)
with MCI patients and caregivers. Two of the studies had overlapping samples, but looked at
MCI participant (Joosten-Weyn Banningh et al. 2011) and caregiver outcomes (Joosten-
Weyn Banningh et al. 2013) separately and so both reports are included in separate table
rows (see Table 5).
Of the 10 multimodal intervention studies reviewed, seven were RCTs and three were CTs.
The study by Reuter et al. (2012) did not include a CG, and instead analyzed subjects
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randomly assigned to incremental levels of intervention (N = 223). MCI patient multi-modal

IG sizes ranged from 6 to 132 (M = 56.5, SD = 39.0); one study analyzed caregivers in an IG
with sample size of 58 (Joosten-Weyn Banningh et al. 2013). Two studies analyzed
intervention groups with sample sizes of 100 or greater (Reuter et al. 2012; Tsolaki et al.
2011; Lam et al. 2015). Control group sizes ranged from 5 to 131 (M = 43.8, SD = 40.8) and
an additional caregiver control group included of 27 participants.
Recruitment rates were examined in 7 of 10 studies (excludes Kurz et al. 2009; Hwang et al.
2012; Reuter et al. 2012). Rates ranged from 4.8 % (Fiatarone Singh et al. 2014) to 89.8 %
(Tsolaki et al. 2011) of approached participants (M = 54.4 %; SD = 31.2). The former study
was a clear outlier; in that study a large participant pool (N = 2094) was approached and
only 100 eligible enrolled (4.8 %). Excluding this study, the average enrollment rate is
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64.3 % (SD = 21.9 %). Two studies (Kurz et al. 2009; Tsolaki et al. 2011) did not publish
data on participants lost to attrition. The average participant retention rate was 85.7 % (SD =
9.0 %).
The average duration of intervention was 16.6 weeks (SD = 14.2) and ranged from 4 weeks
(Kurz et al. 2009; Reuter et al. 2012) to 52 weeks (Lam et al. 2015). An average of 52.2 h of
intervention (SD = 49.0) was delivered across the 10 studies. Five studies (Fiatarone Singh
et al. 2014; Hwang et al. 2012; Joosten-Weyn Banningh et al. 2011; Law et al. 2014; Reuter

et al. 2012) provided data from post-intervention follow-up assessments with intervals
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ranging from two to 52 weeks (M = 23.0, SD = 15.6), and Hwang et al. (2012) also
followed-up with participants at three months post intervention.
Four studies combined cognitive training with physical exercise (Fiatarone Singh et al. 2014;
Kurz et al. 2009; Lam et al. 2015; Reuter et al. 2012). Three studies used interventions with
a combination of cognitive strategy training, psychoeducation, and social skills training
components (Joosten-Weyn Banningh et al. 2011; Joosten-Weyn Banningh et al. 2013;
Schmitter-Edgecombe and Dyck 2014). Two studies (Hwang et al. 2012; Law et al. 2014)
utilized interventions with computerized and non-computerized cognitive training
components. One study (Tsolaki et al. 2011) provided varying methods of non-computerized
cognitive training (e.g., paper-and-pencil tasks, prospective memory training, etc.). Reuter et
al. (2012) assigned groups to one of the following interventions: one group received
cognitive training, relaxation, and occupational therapy; one group with the previously stated
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components plus a training skills application session; and one group with cognitive training,
application session, and additional motor skills training.
Meta-Analysis
Overall Effects—A subset of six of the 30 articles reviewed could not be used, in whole or
in part, in our meta-analysis due to failure to include sufficient information to compute
standardized mean differences; of these, four papers contributed no information to the meta-
analysis (Belleville et al. 2006; Fiatarone Singh et al. 2014; Finn and McDonald 2011;
Reuter et al. 2012), and two contributed only one or two outcomes because of a lack of
information about other outcomes in their paper (Hwang et al. 2012; Rojas et al. 2013).
Sample sizes included in the meta-analysis were smaller than the original, randomized
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sample sizes described above due to attrition by the most distal follow-up occasion utilized
in the meta-analysis. Tables 2, 4, and 6 show the effect sizes for the studies included in the
meta-analysis along with the residual treated and control sample sizes employed in the meta-
analysis.
The mean effect size (d) representing the omnibus difference between improvement in the
treatment versus control group was 0.21 in the fixed effects model (95 % confidence interval
= 0.16–0.27, SE = 0.03), which was significantly different from zero (z = 7.50, p < .001,
based on 91 outcome measures), with the Q-statistic indicating significant heterogeneity in
effect size (χ2 [90] = 185.88, p < .001). In the random effects model, the mean effect size
representing the difference between improvement in the treatment versus control group was
0.26 (95 % confidence interval = 0.17–0.35, SE = 0.05), which was significantly different
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from zero (z = 5.71, p < .001, based on the same 91 outcome measures). The Q-statistic, in
contrast, indicated homogeneity in effect size (χ2[90] = 78.54, p = .80). The tau estimate of
variance in population effect size was 0.08. Rejection of the null hypothesis of homogeneity,
at least in the fixed effect model, suggests that moderator models are indicated.
Variation in Effect Sizes by Treatment Modality and Outcome Type—Two tests

for subgroup differences were conducted. The first examined differences between therapy
type (i.e., computer administered, therapist administered, and multi-modal). The fixed effect

model indicated that this difference was significant (χ2 [2] = 8.56, p = .01). Table 7 displays
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the number of outcomes (k), mean standardized effect size (d), 95 % confidence interval,
tau-squared (τ2), and p-value for the Q-test assessing the null hypothesis of homogeneity
within each therapy type as well as for each outcome category type. In all instances, the
random effects models could not reject the null hypothesis of homogeneity, meaning that
results were consistent within studies using similar intervention approaches. For all three
intervention types, treatment effects were positive (average d statistics ranged between 0.20
and 0.31, corresponding to a “small” effect size) and significantly different from zero.
The second comparison of subgroup differences examined differences between outcome

type (i.e., mood, meta-cognition, ADL, and QOL). The fixed effect model indicated that this
difference was also significant (χ2 [3] = 14.75, p = .002). Reviewing the results in Table 7,
for each of the four outcome types, the random effects models could not reject the null
hypothesis of homogeneity, meaning that results were consistent within a group of
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outcomes. For mood, metacognition and ADLs, treatment effects were positive (average d
statistics ranged between 0.16 and 0.37, corresponding to a “small” or “small to medium”
effect size) and significantly different from zero. For QOL, average effect size was not
different from zero.
We examined stem-and-leaf plots broken down by the intervention approach, and by

outcome type. While the average standardized mean differences in most intervention
modalities and outcome categories show clear evidence of symmetrical cluster, the averages
may be biased upwards by positive skew. Thus, we also determined the, median effect sizes
by therapy type were: mediancomputer = 0.17; mediantherapist = 0.23; medianmultimodal = 0.23.
Median effect sizes by outcome category were: medianmood = 0.16; medianmetacognition =
0.30; medianADL = 0.23; medianQOL = 0.10. Once at the level of examining outcome
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category by intervention approach (e.g., mood outcomes by computerized intervention), the

small number of variables per cell made reporting of aggregate effect size scores unreliable.
Thus, qualitative analysis of these variables was further explored (below).
Computerized Interventions Outcomes

ADLs: Four of the seven studies included an assessment of basic and or instrument ADLs.
No study reported a significant benefit to ADLs from cognitive training.
Mood: Four studies included a mood measure. Two of three studies employing the Geriatric
Depression Scale (GDS; Yesavage et al. 1983) reported improved scores on this instrument.
Two studies employing the State Trait Anxiety Inventory, State Scale (Spielberger 1983)
reported improved scores on this instrument. In one of those studies end of treatment
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findings were negative but 12 month follow-up findings were positive. In a study also
employing the Neuropsychiatric Inventory (Cummings et al. 1994) an informant-based
measure of observed mood and behavior, NPI total was improved due to lower scores of
perceived depression, anxiety, and apathy. Finally, one additional study using an integrated
depression, anxiety, and stress scale (Depression, Anxiety and Stress Scale, DASS-21;
Lovibond and Lovibond 1995) found no impact of computer training in any of these three
domains.

QOL: Only one study (Gagnon and Belleville 2012) included a well-being scale. They
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found no impact of training on this scale.
Metacognitive: In four different studies, participants used five different instruments to

report on their perceptions of cognitive function. In three of those four studies, computer
training did not have an impact on reported cognitive function. In these studies, the cognitive
self-report measures all focused on perception of memory function. Only in Gagnon and
Belleville (2012), where both training and the self-report measure focused on attention, was
there a positive finding.
Summary: Computerized cognitive training in MCI did not appear to impact ADL measures
or measures of self-reported memory function. Evidence for an impact on mood was mixed,
with some studies reporting improvement in depression, anxiety, and perhaps apathy. There
was not enough research to comment on the impact of computerized training on QOL.
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Therapist-Based Interventions Outcomes

ADLs: ADLs were assessed in 10 therapist-based intervention studies, and of those studies,
half found some positive benefit to daily activities (Brum et al. 2009; Greenaway et al. 2013;
Konsztowicz et al. 2013; Rojas et al. 2013; Rapp et al. 2002). There was little overlap in the
measures that were used to determine ADLs, but four studies used the Multifactorial
Metamemory Questionnaire (MMQ; Troyer and Rich 2002) Ability Subscale with only one
finding significant benefit from memory training on that measure (Konsztowicz et al. 2013).
Mood: Mood was assessed in 12 studies, with only three studies reporting significant
change (Buschert et al. 2011; Konsztowicz et al. 2013; Lam et al. 2015). Kinsella et al.
(2009) actually found improved mood over time in their control group contrary to their
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hypothesis. Buschert et al.’s report of mood improvement at training end was diminished by
15-month follow up (2012). There was little consistency in measures used, but four used the
MMQ Contentment Subscale. Similar to the ADL findings, only Konsztowicz et al. (2013)
reported improved contentment in their memory-training group.
QOL: QOL of assessed in six studies, with only two reporting significant improvement after
intervention (Vidovich et al. 2015; Belleville et al. 2006). The most commonly used measure
was the Quality of Life AD (Logsdon et al. 2002), used in three studies, only one of which
was significant (Vidovich et al. 2015).
Metacognitive: Participants’ sense of their memory or memory strategy use was assessed in
10 studies. Six studies had positive results (Belleville et al. 2006; Kinsella et al. 2009; Lam
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et al. 2015; Rapp et al. 2002; Troyer et al. 2008; Vidovich et al. 2015). The MMQ Strategy
Use (self-reported memory strategy use) was the most often cited measure (4 out of the 10
studies).
Other: Greenaway et al. (2013) reported the impact of the intervention on caregivers, with
no effect on caregiver QOL or anxiety, but less sense of caregiver burden and depression
compared to the control group by six months post intervention. Buschert et al. (2012)
reported that 6 out of 12 of their CG had converted to dementia by eight months post, while

none of their IG had converted. Vidovich et al. (2015) found that 6.7 % of their CG and
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11.9 % of their IG had converted to dementia at two years, but 45 % of their CG and 37 % of
their IG group had reverted to normal by two year follow-up.
Summary: The strongest evidence for everyday impact of therapist-based interventions was
for the improvement of metacognitive aspects of memory. After these cognitive
interventions, individuals with MCI believed they knew more strategies to help with their
memory and/or had more sense of self-efficacy surrounding their memory function.
Additionally, about half of studies demonstrated positive impact on ADLs, particularly when
practical compensation strategies were taught. This translated into little evidence for
improving mood or QOL in the participant with MCI, but there may be some positive
caregiver outcomes.
Multimodal Interventions Outcomes

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ADLs: Six of the 10 multimodal intervention studies assessed ADL outcomes, of which four
reported significant improvements. Two studies saw improvement on ADL rating scales with
cognitive plus physical interventions (Kurz et al. 2009; Lam et al. 2015) and one saw
positive impact with cognitive plus psychological interventions (Tsolaki et al. 2011).
Schmitter-Edgecombe and Dyck (2014), using cognitive plus psychological interventions,
found improvements on performance-based measures of ADLs involving bill-paying and
money management activities. Two studies utilizing the Bayer-ADL scale (B-ADL;
Hindmarch et al. 1998) saw inconsistent improvement. One study using both computerized
and non-computerized cognitive training (Law et al. 2014) provided follow-up analyses that
showed no sustained improvement in ADLs at 6-months follow-up.
Mood: Mood outcomes were mixed (assessed in 4/10 studies), with two cognitive plus
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physical interventions (Kurz et al. 2009; Lam et al. 2015) showing improvement, and two
cognitive plus psychological interventions (Joosten-Weyn Banningh et al. 2011; Schmitter-
Edgecombe and Dyck 2014), showing no improvement upon intervention end. The two
studies that did not find improvements in mood used a short form version of the GDS
(Yesavage et al. 1983). No study assessed mood at a post-intervention follow-up.
QOL: QOL was assessed in four of the studies (Hwang et al. 2012; Joosten-Weyn Banningh
et al. 2011; Reuter et al. 2012; Schmitter-Edgecombe and Dyck 2014), and most of these
studies identified no impact. QOL improved in a cognitive plus psychological training
intervention (Joosten-Weyn Banningh et al. 2011) using the RAND-36-Dutch (Van der Zee
and Sanderman 1993). In this study, the Helplessness subscale of the Illness Cognition
Questionnaire (ICQ; Evers et al. 2001) was sensitive to change following the intervention;
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however, the ICQ Acceptance subscale did not show improvement. The intervention group
from Reuter et al. (2012) received the most intensive treatment (i.e., cognitive and motor
training with practice) saw QOL improvements. No lasting impact on QOL was seen at 2-
week or 3-month follow-up intervals.
Metacognition: Metacognitive outcomes were assessed in four of the 10 studies with

generally improved outcomes. Hwang et al. (2012) showed improvement using a

computerized plus non-computerized cognitive intervention on a self-assessment of

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cognition scale at 2-week follow-up; however, these improvements were not sustained at
three months. Multi-modal interventions showed positive impact on self-reported and
informant based cognitive complaints (Lam et al. 2015; Joosten-Weyn Banningh et al. 2011)
but not in self-reported coping self-efficacy (Schmitter-Edgecombe and Dyck 2014).
Other: Two studies using cognitive plus psychological interventions analyzed the impact on
mood, QOL, and metacognition in caregivers (Schmitter-Edgecombe and Dyck 2014;
Joosten-Weyn Banningh et al. 2013). No improvements were found for mood, but one scale
of well-being indicated an improvement in QOL of caregivers (Joosten-Weyn Banningh et
al. 2013). Positive findings were found on scales of coping self-efficacy (Schmitter-
Edgecomb and Dyck 2014) and awareness of the MCI participant’s cognitive symptoms
(Joosten-Weyn Bannigh et al. 2013).
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Summary: Although more studies found no impact on ADLs than benefit; the
improvements in ADLs were seen mostly in the cognitive plus physical interventions
studies. Mood improvements, particularly for depression, were mixed overall. But again, the
studies that found improvements in mood were cognitive plus physical interventions. There
was little evidence for impact of multimodal interventions on QOL. Metacognitive outcomes
were generally positive across multi-modal interventions. Preliminary evidence suggests
potential positive benefit in caregiver outcomes when cognitive plus psychotherapy
interventions are used. Overall, the most favorable outcomes tended to be in multimodal
studies that combined interventions with cognitive and physical training.
Publication Bias—For the overall corpus of studies, Rosenthal’s Fail Safe N was 2295,
indicating that there would need to be 2.295 unpublished studies not included in the meta-
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analysis to make the population effect size non-significant. Begg and Mazumdar’s rank
correlation (tau) was .17 (p = .02) indicating small but non-trivial publication bias. Random-
effects weighted effect size estimates under the conditions of ‘moderate one-tailed
selection’, ‘severe one-tailed selection’, ‘moderate two-tailed selection’, and ‘severe two-
tailed selection’ were 0.15, −0.84, 0.21 and 0.16 respectively; this pattern of results suggests,
congruent with our confidence interval and stem-and-leaf information noted earlier, that the
overall average effect of 0.26 may be positively biased.
For the moderator analyses examining variation in effects by therapy modality and outcome
type, we have included the publication bias statistics in Table 7. In general, these findings
suggest that for the three different intervention types and four different outcome types, the
results are affected by mild publication bias.
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Discussion
Cognitive interventions in MCI have received increased interest from the international
research community. Our review of the literature suggests that cognitive interventions in
MCI have the potential for positive impact, but as previous authors have suggested (Cooper
et al. 2013; Gates et al. 2011; Kurz et al. 2011), the heterogeneity of interventions and
outcome measures used make it difficult to determine the everyday impact.

By looking at trends across studies, we can speculate what the potential impact might be.
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First, an overall meta-analysis combining all intervention and outcome types suggests that
cognitive interventions in MCI cohorts have a small, positive effect on everyday outcomes.
Therapist-based, computer-based, and multi-modal interventions all appear to have small but
significant effects on everyday outcomes. These effects are seen in mood, ADL and meta-
cognition measures but, at least for the studies included here, not in QOL outcomes. The
effect size estimates reported here were likely conservative, as we used the most distal
follow-up occasion available, which may have reduced the estimated effect sizes due to
treatment effect dissipation over time.
Computerized interventions tend to be more restitution based, focus more on post-training

cognitive outcomes, and are suspected to have limited far transfer to everyday measures
(Coyle et al. 2015). However, in this review, participation in computerized cognitive
interventions appeared to have the potential to positively impact mood. Some studies report
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improvement in depression, anxiety, and perhaps apathy. There was little evidence for
improved mood from therapist-based cognitive training interventions.
When the intervention takes place with a therapist, either individually or in a group format,
positive impact on ADLs is more often observed. Computer based interventions did not
impact ADLs. The focus of therapist interventions is more often on compensation strategies
(either internally-based mnemonic strategies or externally-based aids such as calendars).
Perhaps this focus translates more readily to daily activity ability, as has been suggested
previously (Rodakowski et al. 2015). Therapist-based interventions also have promise for
improvement of metacognitive aspects of memory, such as how equipped a person feels with
regard to strategies to combat memory loss, and/or use memory strategies (i.e., memory self-
efficacy). There was little evidence of benefit to metacognitive variables from computerized
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training.
Recently, studies of multimodal interventions have emerged into the literature. These
interventions seek to explore the benefits of cognitive interventions combined with other
promising nonpharmacological interventions like exercise and socialization/psychotherapy.
Many of these studies have employed therapist-based interventions, and the findings of
impact on ADLs, mood, and metacognitive variables largely mirror the single-modality
cognitive intervention literature. Combining physical and cognitive interventions appear to
be particularly beneficial.
There was an absence of QOL effects affects across cognitive interventions. This likely
reflects several factors. First, QOL is a complex construct with many inputs (e.g., health,
economic status, and social factors), so cognitive interventions might have only partial
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effects. Secondarily, interventions have investment costs; they are effortful, demanding of
time, and may expose weaknesses that participants were not previously aware of prior to
being challenged by training exercises. All of these could be expected to have negative
impacts on reported QOL, particularly at the follow-up period immediately after treatment.
It should be noted that these studies employed cognitive interventions. It may be that the
inclusion of more direct “training for transfer” (i.e., including cognitive intervention

exercises that specifically address outcomes like ADL, mood, metacognition and QOL rather
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than targeting cognition itself) may have further strengthen treatment generalization.
In this updated review, we sought to explore whether prior admonitions for this area of
research to employ larger trials, RCTs, and consistency in outcomes have been heeded.
Newer studies, particularly multimodal intervention studies, have used larger samples,
although the average number of individuals in each arm of trials still averages less than 30.
Only a few studies report sample sizes in the hundreds. Our review is encouraging that more
studies with larger samples are appearing. It is also encouraging that in these trials
recruitment rates (M = 58 %) and retention rates (M = 84 %) are compatible with what is
seen in other clinical trials such as pharmacological trials (Grill and Karlawish 2010) despite
the often significant time commitment.
When we set our inclusion and exclusion a priori for this review, we did not limit to RCTs,
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but allowed CTs for inclusion. We actually found that a good number of recently conducted
trials were RCTs. The field appears to be progressing beyond small, uncontrolled feasibility
studies into larger RCTs. Because of this, future reviews can likely limit their analyses to
RCTs
Consistency in interventions and outcome variables remain key issues to overcome in this
literature. Most researchers appear to have created their own unique sets of cognitive
interventions and outcome measures. Many past studies were likely happening at the same
time, inspired by the few early works. Thus, unless they adopted outcome measures from
these first few studies (e.g., using the MMQ as Kinsella et al. 2009, and Troyer et al. 2008,
did in their early works), researchers were utilizing unique measures based on their own
experiences and research. Moreover, the locations where this research was conducted
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(presented in Tables 1, 3, and 5) reflect just how international the research on cognitive
interventions for MCI truly has become. The global nature of this effort likely also
contributes to the variety of interventions and outcomes as multiple cultures and languages
seek to address cognitive rehabilitation in MCI.
The commonly used measures in this area of research can be found in Tables 2, 4, and 6. For
ADLs, we frequently saw the BADL (Hindmarch et al. 1998) used. The second most
commonly used measure of ADLs was the Clinical Dementia Rating Scale (CDR). The GDS
(Yesavage et al. 1983) was most often used in assessing mood, and more specifically,
depressive symptom outcomes. QOL was assessed most commonly with the Quality of Life-
Alzheimer’s disease (Logsdon et al. 2002). Metacognitive outcomes were most often
examined with the Memory Functioning Questionnaire (MMQ; Gilewski et al. 1990) or the
Metamemory Questionnaire (MMQ; Troyer and Rich 2002). The MMQ is one of the most
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widely used instruments in general. This measure has subscales that examine ADLs (MMQ
Ability) and mood/QOL (MMQ contentment), so researchers often present all of these
aspects in their results. These instruments provide a good starting point to know what may
be useful in finding effect (e.g., the MMQ metacognitive scales), and those that perhaps may
be insensitive to finding change in the MCI population (e.g., the CDR may not sample
enough higher level ADLs). Other reviews further point out methodological steps that could

add consistency to cognitive intervention research in MCI (Hampstead et al. 2014; Huckans
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et al. 2013).
Our systematic review and meta-analysis is limited by searching only MEDLINE and
PsychInfo databases. Thus, some studies may have been missed. We also excluded four non-
English studies due to our limited resources to translate them into English. Additionally, we
were unable to solicit missing information from 6 studies to complete effect sizes and
include them into the meta-analysis. Our findings may have been different had these
additional studies/variables been added.
Further, we allowed for the inclusion of both CTs and RCTs in this review. We found that
while most studies used a no-treatment control group, other studies, particularly the
computer-based interventions, at times used suspected active control interventions,
educational series, or even an alternative intervention suspected to not impact cognition in
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the same way as the experimental intervention. The differentiation between what truly was
an active control and to what degree the education or alternative intervention would not
impact cognition or the everyday functioning variable regularly was not well established in
the articles, and was most often solely theoretically based. It is unclear if some impact of
these suspected “active control” interventions may have tempered the effect sizes of these
studies.
A key question in meta-analysis is the issue of publication bias. That is, to what extent might
publication bias lead to an inflated or distorted estimate of true effect sizes? Concerns about
publication bias likely hold for this corpus of thirty studies: (A) We did not solicit
unpublished papers from outside the search databases listed; (B) We did not consult clinical
trials registries to identify additional registered trials that have not been published; and (C)
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Published papers will be biased towards those with significant findings (Coursol and Wagner
1986; Greenwald 1975). However, it is noteworthy that most of the reviewed studies had a
primary aim of having cognitive effects. Thus, most the outcomes considered in this review
were in fact secondary, transfer outcomes for these studies. Often these everyday impact
measures were given only a brief mention in the final paragraph of the results or embedded
in a table without further explanation. This incidental reporting of positive or negative
secondary results may have mitigated publication bias effects to some degree in this meta-
analysis of everyday outcomes.
Indeed, our quantitative explorations of publication bias suggested the presence of relatively
minor positive bias. For the overall set of studies, and for the subgroups of therapy
modalities and outcomes, results suggested that anywhere from three to fifteen times the
number of included studies would have to have been left out for significant d statistics to
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become non-significant. Rank correlation tested indicated generally only small associations
between d and its standard error, suggestive of at most mild bias. Taken together, while
publication bias undoubtedly influences the average effect sizes reported here, we have
reason to believe that the median effect sizes and 95 % confidence intervals (all but one of
which excludes d = 0.00) likely include the true population effect size.

Substantial research is still needed to determine the basic “active ingredients” of cognitive
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training and behavioral interventions in MCI, including the specific and non-specific
treatment effects, dosing (i.e., number of sessions over what time frame), best training
context (e.g., group vs. individual), participant variables affecting specific outcomes, etc.
Further, research into how combining multiple nonpharmacological interventions may have
synergistic impacts on everyday outcomes will perhaps produce the most effective
“treatment sets” for MCI. Ideally, one day it will be possible to tailor treatment plans, using
evidence-based interventions, to the outcomes that patients define as most important to
them. Until then, much more investigation is needed to determine the impact of cognitive
interventions on everyday outcomes in MCI, as, to date, only modest overall effect sizes
were found in this meta-analysis.
Acknowledgments
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Funding
Research reported in this manuscript was partially funded through a Patient-Centered Outcomes Research Institute
(PCORI) Award (CER-1306-01,897). The statements in this publication are solely the responsibility of the authors
and do not necessarily represent the views of the Patient-Centered Outcomes Research Institute (PCORI), its Board
of Governors or Methodology Committee.
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Appendix
Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid

MEDLINE(R) 1946 to Present
1. mild cognitive impairment/ or (mci or amci or mci-a or predement* or pre-
dement* or pre-AD or (mild adj2 cogniti* adj2 (decline or impair* or
deficit* or deteriorate* or disorder*)) or ((prelude or preclinical or pre-
clinical or prodromal or precursor) adj2 (dement* or Alzheimer* or
Author Manuscript
AD))).tw
2. rh.fs or cognitive therapy/ or ((cogniti* or behavi* or memory or attention

or information or neuropsychological or rehearsal* or mnemonic) adj3
(intervention* or rehab* or program* or strategy* or train* or retrain* or
treatment* or therapy or therapies or stimulat* or technique*)).tw
3. 1 AND 2
4. limit 3 to (addresses or autobiography or bibliography or biography or

case reports or classical article or comment or dictionary or directory or
editorial or historical article or in vitro or interactive tutorial or interview
or legal cases or legislation or letter or news or newspaper article or patient
Author Manuscript
education handout or periodical index or portraits or technical report)
5. 3 NOT 4
6. (infant* OR infancy OR newborn* OR baby* OR babies OR neonat* OR

preterm* OR prematur* OR postmatur* OR child* OR schoolchild* OR
school age* OR preschool* OR kid or kids OR toddler* OR adoles* OR
teen* OR boy* OR girl* OR minors* OR pubert* OR pubescen* OR
prepubescen* OR paediatric* OR paediatric* OR peadiatric* OR nursery
school* OR kindergar* OR primary school* OR secondary school* OR
elementary school* OR high school* OR highschool* or youth).tw
7. 5 NOT 6
8. 7 not (exp neoplasms/ or epilepsy/ or (schizophren* or cancer* or

Author Manuscript
neoplas* or epilep*)).tw.
9. (treatment outcome/ or treatment failure/ or quality of life/ or activities of

daily living/ or mental recall/ or (outcome* or efficac* or effectiv* or
benefit* or ( (daily adj2 activit*) or (self* adj care*1))).tw. or ((pre* or
post*) adj interven*).tw)
10. 8 AND 9

PsychInfo 1967 to October Week 3 2015

Author Manuscript
1. (mci or amci or mci-a or predement* or pre-dement* or pre-AD or (mild

adj2 cogniti* adj2 (decline or impair* or deficit* or deteriorate* or
disorder*)) or ((prelude or preclinical or pre-clinical or prodromal or
precursor) adj2 (dement* or Alzheimer* or AD))).tw
2. exp. cognitive techniques/ or exp. neuropsychological rehabilitation/ or

((cogniti* or behavi* or memory or attention or information or
neuropsychological or rehearsal* or mnemonic) adj3 (intervention* or
rehab* or program* or strategy* or train* or retrain* or treatment* or
therapy or therapies or stimulat* or technique*)).tw.
3. 1 AND 2
Author Manuscript
4. NOT (infant* or infancy or newborn* or baby* or babies or neonat* or

preterm* or prematur* or postmatur* or child* or schoolchild* or school
age* or preschool* or kid or kids or toddler* or adoles* or teen* or boy*
or girl* or minors* or pubert* or pubescen* or prepubescen* or
paediatric* or paediatric* or peadiatric* or nursery school* or kindergar*
or primary school* or secondary school* or elementary school* or high
school* or highschool* or youth).tw.
5. limit 4 to (bibliography or “column/opinion” or “comment/reply” or

editorial or encyclopedia entry or letter or obituary or poetry or
publication information or reprint or review-book or review-media or
review-software & other or reviews)
6. 4 NOT 5
Author Manuscript
7. AND (treatment outcomes/ or treatment effectiveness evaluation/ or exp.

quality of life/ or exp. activities of daily living/ or exp. recall learning/ or
(outcome* or efficac* or effectiv* or benefit* or ((daily adj2 activit*) or
(self* adj care*1))).tw or ((pre* or post*) adj interven*).tw.)
8. not (exp neoplasms/ or epilepsy/ or (schizophren* or cancer* or neoplas*

or epilep*)).tw.
Author Manuscript

Author Manuscript
Fig. 1.
Cumulative growth of controlled trials of cognitive interventions in MCI over time. To fully
illustrate the total number of studies in this area, studies that included no generalization
outcome measure (i.e., controlled trials of cognitive interventions in MCI that only provided
Author Manuscript
cognitive measures or fMRI outcomes) that were excluded from the general review are
shown in this figure as “Non-gen outcome”
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Fig. 2.
PRISMA Flow Diagram. Flow diagram illustrating the process of inclusion/exclusion of
studies
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Author Manuscript Author Manuscript Author Manuscript Author Manuscript
Table 1
Overview of Computerized Intervention Studies
Reference/Location Type IG CG Recruitment/Attrition Intervention(s) Sessions/Duration Follow-up Cognitive Outcomes

Fiatarone Singh et al. RCT Recruitment: 2094 COGPACK® computer 2–3 sessions per 6 months No significant improvement
Chandler et al.
MCIa (n MCIa
(2014); Australia = 24) Sham cognitive Approached 2,094 research program: adaptive week for 6 months or (intervention
activity and participants, 1994 Not exercises of memory, EF, 52–78 sessions end)
exercise ineligible (1582 not attention, and processing 60–100 minutes 18 months (12
control interested, 217 on hold, 117 speed, and sham months post
condition (n = ineligible, 61 no contact, 17 physical training intervention)
27) withdrawals), 100 enrolled
Attrition: 14 dropped out
before intervention, 12
dropped out after
intervention
Finn & McDonald RCT aMCIb aMCIb single Recruitment: 27 people Lumosity program 30 sessions, for 6 Intervention end Improved visual sustained
(2011); Australia single and multiple recruited from memory weeks attention, no treatment effect
and domains clinic 2 excluded prior to on visual learning,
multiple Waitlist (n = 8) randomization, 12 recognition, working
domains randomized to intervention, memory or set shifting
(n = 8) (3 withdrawals in IG, 1
additional exclusion), 13 to
control, (4 withdrawals 1
additional exclusion)
Attrition: None
Gagnon & Belleville RCT MCIa (n MCIa Recruitment: Approached 79 Variable priority 6 sessions 1 hour Intervention end Both groups improved on
(2012); Canada = 12) Active candidates from memory attention training sessions spread of 2 focused attention, speed of
computer disorders clinics, 53 weeks processing, and switching
training (n = excluded, 26 randomized, 13
12) randomized to each group
Attrition: 2 did not complete
Gaitan et al. (2013); RCT aMCIa aMCIa single Recruitment: 60 candidates Group-based FesKits 30 sessions 30- 3 months No significant improvement
Spain single and multiple randomly selected from pool computer program minute computer 12 months
and domains. of 93 interested, 37 sessions embedded in
multiple Traditional randomized to intervention 1-hour traditional
domains cognitive (6 refused or did no cognitive therapy
(n = 23) training (n = complete baseline), 23 to session

16) control (3 refused or did not
complete baseline
Attrition: 11 withdrew prior
to 3-month f/u; 1 outlier in
each group excluded
Hughes et al. (2014); RCT MCI (n = MCI Recruitment: Approached Group-based 24 session, 90 minute Intervention end CAMCI
USA 10) Healthy aging MYHAT participants, 445 Nintendo Wii™ video weekly sessions for 1 year 24 weeks/+
education (n = eligible, 128 initially game 24 weeks 1 year/−
10) interested, 91 contacted 71
excluded (not interested,
unable to contact, ineligible,
not available)
Page 28

Rozzini et al. (2007); RCT aMCIa (n aMCIa No information TNP computer program 3 blocks of 20 1 year Improvements in story
Italy = 15) AChEI only (n 1-hr sessions, 60 memory and abstract
= 22) total sessions for 9 reasoning§
months
aMCIa
No treatment
Chandler et al.
(n = 22)
Talassi et al. (2007); CT MCIa (n MCIa Recruited from a day TNP computer program, 12 sessions Intervention end No significant improvement
Italy = 30) Non-cognitive rehabilitation hospital occupational therapy of 4 days per week for 3
activities ADLs, and behavioral weeks
(physical therapy
therapy,
occupational
therapy, and
behavioral
therapy) (n =
7)
Note. MCI criteria used:

a
Petersen et al., 1999 or 2004;
b
Winblad et al., 2004;
c
Albert et al., 2011;
d
Morris, 1993;
e
Portet et al., 2006.
AChEI = Acetylcholinesterase inhibitor. aMCI = Mild cognitive impairment, amnestic subtype. CG = control group. CT = Controlled trial. f/u = Follow-up. IG = Intervention group. MCI = Mild cognitive
impairment. RCT = Randomized controlled trial.
§
Within-subjects change.
Interventions: COGPACK® (Marker 2008). FesKits (Fundacio Privada Espai Salut 2009). Nintendo Wii™ (Nintendo of America Inc., Redmond, WA). TNP (Sinforiani et al. 2004).

Measures: CAMCI (Computerized Assessment of Mild Cognitive Impairment; Saxton et al. 2009)
Page 29
Table 2
Everyday Outcomes for Computerized Intervention Studies
Reference ADLs Mood QOL Metacognition Other

Fiatarone Singh et al. (2014) Bayer-ADL/−
Chandler et al.
Finn and McDonald (2011) DASS-2 Subtests: MFQ/−

Depression/− MCI/−
Anxiety/−
Stress/−
Gagnon and Belleville (2012) WBS/− DAQ/+
(d = 0.16, 12, 12) (d = −0.26, 12, 12)
Gaitan et al. (2013) GDS MFEM
3 month/− 3 months/−
12 month/− 6 months/−
STAI-State (d = 0.56, 23, 16)
3 month/−
12 month/+
(d = 0.16, 23, 16)
Hughes et al. (2014) Timed IADL/− CSRQ-25: − Walking speed: −
(d = −0.12, 10, 10) (d = 0.89, 10, 10)
Rozzini et al. (2007) BADL/− GDS§/−
(d = 0.18, 15, 25) (d = 0.17,15,15)
NPI§/+
(d = 0.84,15,15)
Talassi et al. (2007) BADL/− GDS§/+ Physical performance test/−
(d = 0.0, 30, 7) (d = 0.20,30,7)
IADL/−
(d = 0.0, 30, 7) STAI§/+
(d = 0.09,30,7)
NPI§/+
(d = 0.84,30,7)
Note. Measures are provided with + or − to reflect whether the outcome was significant. When it was possible to calculate effect size, those numbers are provided next to the relevant test (effect size, final
number of participants treated by that time point, final number of comparison participants by that time point). Positive effect sizes reflect greater improvement for treatment group relative to comparison

group). Outcomes without an effect size did not provide information necessary to compute standardized mean differences.
§
Within-subjects change.
Measures: BADL (Bayer-Activities of Daily Living; Hindmarch et al. 1998); CSRQ (Cognitive Self-report Questionnaire; Spina et al. 2006); DASS-21 (Depression Anxiety Stress Scale; Lovibond and
Lovibond 1995); DAQ (Divided Attention Questionnaire; Tun and Wingfield 1995); GDS (Geriatric Depression Scale; Yesavage et al. 1983); IADL (Instrumental Activities of Daily Living; Lawton and
Brody 1969); MCI (Memory Controllability Inventory; Lachman et al. 1995); MFEM (Memory Failures in Everyday Memory; Sunderland et al. 1984); MFQ: (Memory Functioning Questionaire; Gilewski
et al. 1990); NPI (Neuropsychiatric Inventory; Cummings et al. 1994); STAI (State Trait Anxiety Inventory; Spielberger 1983); WBS (Well-Being Scale; Bravo et al. 1996).
Page 30
Table 3
Overview of Therapist-based Intervention Studies

Belleville et al. CT Recruitment: No information Group-based 8 weekly sessions of Intervention end Improved performance
Chandler et al.
aMCIa (single or aMCIa Waitlist

(2006); Canada multi domain) (n (n = 8) Attrition: 2 did not complete, Combination of 120 minutes on face name association
= 17) 1 excluded from analysis education on the and word list delayed
from arthritis that interfered aging brain, memory tasks for IG, no
with testing; computerized change in paragraph
CG: no loss attention training, learning (study specific
and in person tasks)
mnemonic training
with homework,
stress management
and “self-efficacy”
were also addressed
Buschert et al. (2011) RCT 2011: aMCIa (n 2011: active (n Recruitment: 27 screened, 3 Group-based 20 sessions 15 months IG improved from
& (2012); Germany = 10) = 12) chose not to participate prior Cognitive training 2 hour sessions per 28 months baseline in global
2012: f/u: (n 2012: f/u (n to randomization, 24 recruited class with multiple week for 6 months cognitive functioning to
=10) =10) Attrition: 2 did not complete, techniques, 28 months post
2 withdrew due to AD including mnemonic intervention, immediate
conversion, lack of interest training and memory improved at 15
prior to 15 and 28 month f/u “informal activities” and 28 mo. f/u; different
to foster cognitive from CG in global
and social skills cognitive functioning at
15 mo. f/u
Brum et al. (2009); RCT MCIa (n = 16) MCIa (n = 18) Not reported Group-based 8 sessions, 2 hours Intervention end IG had significant
Brazil Received Education and per session, 2 improvement compared
intervention mnemonic training sessions per week for to CG for attention
after final data with time spent in one month
collection session on
orientation, face-
name associations,
visual/auditory
attention exercises,
mnemonics, and
ADL practice

Finn and McDonald RCT aMCIb (single or aMCIb (n = 12) Recruitment: 31 recruited Individual-based Practice round plus Intervention end Improvement in memory
(2015); Australia multi) (n = 12) Minimal Attrition: 4 withdraw after Repetition lag six training sessions for non-training word
contact for randomization but before training in learning (long enough to pairs in IG, but no effect
measure treatment due to medical/ words and complete 4 rounds of on attention,
completion personal issues, 2 did not discriminating them training), 5 weeks concentration, or speed
meet diagnosis criteria, 1 from incorrect maximum tasks
could not complete in 5 “lures” that are then
weeks repeated at
increasing lengths
of time as the
participant does
well
Page 31

Greenaway et al. RCT aMCIa single aMCIa Recruitment: 61 contacted, 21 Individual-based 12 sessions, 1 hour 8 weeks No change in global
(2013); USA domain (n = 18) Calendar with declined (most often due to Training of use of each, for 6 weeks 6 months cognitive functioning
no training (n = driving distance to facility) the Memory
17) Attrition: 2 withdrew prior to Support System
intervention, 1 withdrew calendar and note
before 8 week f/u, 2 withdrew taking external aid
Chandler et al.
prior to 6 month f/u

Jean, Simard, et al. RCT aMCIa (n = 11) aMCIa Active Recruitment: 22 total (no Individual-based 6 sessions, 45 4 weeks Both groups improved in
(2010); Canada time matched details given) Training of 10 faces minutes each, for 3 ability to learn face-name
(n = 9); both Attrition: 2 lost in CG during with names weeks associations (same list as
groups had training (overburdened with Experimental = face trained)
additional work = 1, travel = 1) name associations
memory with errorless
education learning and spaced
retrieval
Control = trained
with errorful
learning
Kinsella et al. (2009); RCT aMCIab (n = 22) aMCIab Recruitment: 89 total referred Group-based 5 sessions, 1.5 hour 2 weeks IG significantly
Australia Waitlist (n = (not interested (12), no time Memory education groups, once a week 4 months improved prospective
24) at 2 week (9), could not contact (4), and practice of for 5 weeks memory task of
f/u poor English 2; 8 used for mnemonic and addressing an envelope at
4 month f/u (n pilot sample; 54 enrolled external aid f/u
= 22) Attrition: 10 withdrew prior practices
to 4 month f/u
Konsztowicz et al. RCT MCI (n = 8 MCI Recruitment: 50 approached Small group 7 sessions, 90 Intervention end Improved delayed word
(2013); Canada memory 4 waitlist (re- as eligible (8 could not be First session minute, 1 session per list recall in memory
training), (n = 7 randomized 2 contacted, 18 not interested, 5 memory didactic; week compensation group for
memory each to too busy, 1 death). Memory training unknown reason
compensation) interventions Attrition: 3 withdrew (MT = 1 intervention =
after 6 months) no longer interested, 1 mnemonics;
couldn’t hear sessions; MC = memory
1 disappointed with compensation =
randomization memory notebook
Lam et al. (2015); RCT MCIb (n = 145) MCIb Recruitment: 655 approached Group-based 3 1-hour sessions per Intervention end IG showed improvement
Hong Kong Social (active) at senior centers, 100 not Cognitively- week, for 12 months over time on global
(n = 131) eligible, 555 enrolled demanding activities cognitive scores, delayed
Attrition: 132 did not (e.g. reading and memory, and verbal

complete discussing fluency
newspaper, board
games, playing an
instrument)
Nakatsuka et al. RCT MCId (n = 32) MCId Recruitment: 295 community- Questions, puzzles, 24 1-hour sessions Intervention end IG improved in global
(2015); Japan Social (active) dwelling older adults and games targeting for 12 weeks (12 cognitive function,
(n = 38) approached; 127 agreed attention and weekly group processing speed and
Attrition: 34 did not complete executive function sessions, 12 weekly verbal fluency
at-home sessions)
Rapp et al. (2002); RCT MCIa (n = 9) MCIa (n = 10) Recruitment: 168 interested, Group-based 6, 2 hour weekly 6 months No significant change on
USA After 6 months By 6 months (n 77 eligible for testing. 43 too Education on group meetings cognitive testing.
(n = 7) = 9) impaired. 25 people memory/dementia,
Page 32

approached, 19 agreed to relaxation,
participate workbook
Attrition: 3 withdrew before 6 assignments,
month f/u mnemonic strategies
Rojas et al. (2013); RCT MCIa (n = 15) MCIa Recruitment: 120 referred, 67 Group-based 2 hour sessions, 2 6 months Decline in CG in global
Chandler et al.
Argentina completed Waitlist (n = met MCI criteria, 21 not Cognitive sessions per week for cognition, memory
through 12 15) interested in study, 46 Intervention 6 months recognition, and
month f/u randomized Program vs. semantic fluency.
Attrition: 9 left trained group, combination of Improvement in IG in
7 left control group (4 cognitive naming and semantic
converted to dementia, 8 stimulation fluency
“family reasons” 2 medical (socializing),
reasons/death, 2 not cognitive exercises,
interested) cognitive training in
mnemonics, general
information on MCI
and external aids
Troyer et al. (2008); RCT aMCIa (n = 23) aMCIa Recruitment: 68 eligible, 5 Group-based 10 sessions 3 months No impact on objective
Canada Waitlist (n = declined, 9 used in pilot. 54 Combination of 2 hour group sessions memory tasks of face-
22) randomized information, for 6 months name learning, number
Attrition: 3 withdrew before intervention training learning, or wordlist
intervention, 3 did not (both external and learning
complete, 3 withdrew before mnemonic) and
3 month f/u homework practice
Vidovich et al. RCT MCIe MCIe Recruitment: 324 assessed Group-based 10 sessions 10 weeks IG had significantly
(2015); Australia 10 weeks (n = Education (114 ineligible; 50 refused), Cognitive activity 90 minute sessions 1 year better digits forward
77) 10 weeks (n = 160 randomized training strategy for 5 weeks 2 years compared to CG after 2
1 year (n = 77) 79) Attrition: 20 CG lost to f/u with cognitive years, but actual amount
2 year (n = 67) 1 year (n = 77) (13 declined, 3 died, 4 ill); 13 rehab, stimulation, of difference so small of
2 year (n = 60) IG lost to f/u (10 declined, 1 and training uncertain significance
died, 2 ill) elements versus
education group
control

a
Petersen et al. 1999 or 2004;

b
Winblad et al. 2004;
c
Albert et al. 2011;
d
Morris, 1993;
e
Portet et al. 2006.
aMCI = Mild cognitive impairment, amnestic subtype. CG = Control group. CT = Controlled trial. f/u = Follow-up. IG = Intervention group. MCI = Mild cognitive impairment. RCT = Randomized
controlled trial.
Page 33
Table 4
Everyday Outcomes of Therapist-based Intervention Studies

Belleville et al. QAM Subtests
Chandler et al.
Wellbeing*/+
(2006) Personal events/+
Places, Political, social events/+
Conversations/−
Books and movies/−
Slip of attention/−
People/−
Use of objects/−
Actions of perform/−General/−
Buschert et al. MADRS QOL-AD 6/12 in CG (who were
(2011) & (2012) Intervention end/+ Intervention end/− given intervention
15 months f/u/− 15 months f/u/− after 8 months)
24 months f/u/− 24 months f/u/− converted to dementia.
(d = 0.64, 10, 12) (d = 0.51, 10, 12) None in the first IG
converted
Brum et al. (2009) DAFS-R Subtests GDS/−
Orientation/+ (d = 0.53, 16, 18)
(d = 0.93, 16, 18)
Communication/−
(d = 0.07, 16, 18)
Finances/+
(d = 1.30, 16, 18)
Shopping/−
(d = 0.49, 16, 18)
Total/+
(d = 1.30, 16, 18)
Finn and DASS-21 Subtests CFQ/−
McDonald (2015) Depression/− (d = 0.29, 12, 12)
(d = −0.24, 12, 12)
Anxiety/−
(d = −0.26, 12, 12)
Stress/−
(d = −0.32,12,12)

Greenaway et al. E-Cog CES-D QOL-AD Self-Efficacy in MCI* Care Partner
(2013) Intervention end/+ 8 weeks f/u /− 8 weeks f/u /− 8 weeks f/u /− CB
8 weeks f/u /+ 6 months f/u /− 6 months f/u /− 6 months f/u /− 8 weeks f/u /−
6 mo f/u/− (d = −0.04, 18, 17) (d = 0.03, 18, 17) (d = 0.26, 18, 17) 6 months f/u /+
(d = 0.16, 18, 17) REACH QOL AD
8 weeks f/u / − 8 weeks f/u /−
6 months f/u / − 6 months f/u /−
(d = 0.23, 18, 17) CES-D
8 weeks f/u /−
6 months f/u /+
REACH
8 weeks f/u /−
6 months f/u /−
Page 34

Jean, Simard, et al. RBMT MMQ Contentment MMQ Strategy
(2010) 1 weeks f/u / − 1 weeks f/u / − 1 weeks f/u /−
4 weeks f/u / − 4 weeks f/u / − 4 weeks f/u /−
(d = 0.22, 11, 9) (d = −0.12, 11, 9) (d = 0.62, 11, 9)
MMQ Ability
1 weeks f/u / −
Chandler et al.
4 weeks f/u / −
(d = 0.27, 11, 9)
Kinsella et al. MMQ Ability subscale MMQ contentment MMQ Strategy Use
(2009) 2 weeks f/u / − 2 weeks f/u /− 2 weeks f/u /+
4 month f/u / − 4 month f/u /+ 4 month f/u /+
(d = −0.07, 22, 22) improved waitlist (opposite of (d = 0.14, 22, 22)
hypothesized) Strategy Knowledge*
(d = −0.13, 22, 22) 2 weeks f/u /+
4 month f/u /+
(d = 0.24, 15, 16)
Konsztowicz et al. MMQ Ability** MMQ Contentment** MMQ Strategy Use**
(2013) Memory Trained/+ Memory Trained/+ Memory Trained/−
(d = 0.36, 8, 4) (d = 0.94, 8, 4) (d = 1.07, 8, 4)
Memory Compensation/− Memory Compensation/− Memory Compensation/−
(d = −0.04, 7, 4) (d = 0.30, 7, 4) (d = 0.54, 7, 4)
Lam et al. (2015) CDAD/− CSDD/+ MIC/+
(d = 0.13, 115, 101) (d = −0.05, 115, 101) (d = 0.09, 115, 101)
CDR/−
(d = 0.15, 115, 101)
Nakatsuka et al. GDS-SF/− Quality of Life Face
(2015) (d = −0.08, 32, 39) scale*/−
(d = −0.39, 32, 39)
Rapp et al. (2002) MCI Present Ability* MFQ General Functioning
Intervention end/+ Intervention end/−
6 months f/u/ + 6 months f/u/−
(d = 0.69, 7, 9) (d = 0.26, 7, 9)
MFQ Frequency of Forgetting MFQ Seriousness
Intervention end/− Intervention end/−
6 months f/u/ − 6 months f/u/−
(d = −0.09, 7, 9) (d = 0.12, 7, 9)

MFQ Retrospective Functioning MFQ Mnemonic Use
Intervention end/− Intervention end/−
6 months f/u/ − 6 months f/u/+
(d = 0.31, 7, 9) (d = 0.50, 7, 9)
MCI Potential Improvement*
Intervention end/+
6 months f/u/−
(d = 0.55, 7, 9)
MCI Inevitable Decline*
Intervention end/+
6 months f/u/−
(d = 0.15, 7, 9)
MCI Effort Utility*
Page 35

Intervention end/−
6 months f/u/ −
Rojas et al. (2013) CDR**/+ NPI/− QOLQ/−
(d = 0.34, 15, 15)
ADLS/−
Chandler et al.
Troyer et al. (2008) MMQ Ability** MMQ Contentment** Memory strategy knowledge*,**
Intervention end/− Intervention end/− Intervention end/+
3 months f/u/− 3 months f/u/− 3 months f/u/+
(d = 0.81, 23, 22) (d = −0.03, 23, 22) (d = 0.31, 23, 22)
Self-report strategy use during testing*
Intervention end/+
3 months f/u/−
(d = 1.21, 23, 22)
MMQ Strategy Use
Intervention end/+
3 months f/u/+
(d = 0.74, 23, 22)
Vidovich et al. SAILS**/− PHQ-9**/− QOL-AD**/+ MFQ Mnemonics Use**/+ LAQ/−
(2015) (d = −0.14, 66, 60) (d = 0.05, 67, 60) (d = 0.23, 67, 60) IG reported significantly lower use of mnemonics in PAQ/−
daily life (opposite of hypothesized) SNSQ/−
(d = −0.18, 67, 59) 27/60 CG no longer
MCI (reverted) at 2
MFQ General Forgetting**/− years
(d = −0.12, 66, 58) 25/67 IG no longer
MFQ Seriousness of Forgetting/− MCI
MFQ Retrospective Functioning**/− 6 CG and 10 IG
(d = 0.45, 67, 59) converted to dementia
at 2 years
Note. Measures are provided with + or − to reflect whether it was reported as significantly different in the study. When it was possible to calculate effect size, those numbers are provided next to the relevant
test (effect size, final number of participants treated by that time point, final number of comparison participants by that time point, positive effect sizes reflect greater improvement for treatment group
relative to comparison group). Cohen’s d effect size computed as [(posttesttreatment − pretesttreatment) − (posttestcontrol − pretestcontrol)]/(pooled baseline standard deviation of both groups). Outcomes
without an effect size did not provide information necessary to compute standardized mean differences. CG = Control group. f/u = Follow-up. IG = Intervention group.
*
Study-specific measure.

**
Effect sizes computed as group differences in Cohen’s d for published posttest-pretest changes.
Measures: ADLS (Activity of Daily Living Scale; Lawton and Brody 1969); CB (Caregiver Burden; Zarit 1990); CDAD (Chinese Disability Assessment for Dementia; Mok et al. 2005); CDR (Clinical
Dementia Rating; Morris 1997); CES-D (Centers for Epidemiological Studies -Depression; Radloff 1977); CFQ (Cognitive Failures Questionnaire; Broadbent et al. 1982); CSDD (Cornell Scale for
Depression in Dementia; C. Lam et al. 2004); DAFS-R (Direct Assessment of Functional Status; Loewenstein and Bates 1989); DASS-21 (Depression Anxiety Stress Scale; Lovibond and Lovibond 1995);
E-Cog (Everyday Cognition Memory Subtest; Farias et al. 2008); GDS-SF (Geriatric Depression Scale-Short form; Sheikh et al. 1986); LAQ (Leisure Activity Questionnaire; Verghese et al. 2003);
MADRS (Montgomery-Asberg Depression Scale; Montgomery and Asberg 1979); MIC (Memory Inventory for Chinese; Cheong et al. 2006); MFQ (Memory Functioning Questionnaire; Gilewski et al.
1990); MMQ (Multifactorial Metamemory Questionnaire;Troyer and Rich 2002); NPI (Neuropsychiatric Inventory; Cummings et al. 1994); QAM (Questionnaire d’auto-evaluation de la memoire; Van der
Linden et al. 1989); PAQ (Physical Activity Questionnaire; Jamrozik et al. 2000); PHQ-9 (Patient Health Questionnaire-Nine Item; Kroenke et al. 2001); QOL-AD (Quality of Life-Alzheimer’s Disease;
Logsdon et al. 2002); QOLQ (Quality of Life Questionnaire; Machnicki et al. 2009); RBMT (Rivermead Behavioral Memory Test; Wilson et al. 1989); REACH (Resources for Enhancing Alzheimer’s
Caregiver’s Health; Wisniewski et al. 2003); SAILS (Structured Assessment of Independent Living Skills; Mahurin et al. 1991); SNSQ (Social Network Satisfaction Questionnaire; Koenig et al. 1993).
Page 36
Table 5
Overview of Multimodal Intervention Studies

Fiatarone Singh et al. RCT Recruitment: 2,094 Cognitive training: 100 minute session, 6 month Speed and attention mildly
Chandler et al.
MCIa MCIa
(2014); Australia Cognitive Sham research participants COGPACK® adaptive 2–3 sessions per (intervention improved at f/u
training and cognitive approached, 1994 not computerized week, for 6 months end)
physical activity and eligible (1582, not exercises of memory, 18 month (12
resistance exercise (n = interested, 214 on hold, executive function, months post
training (n = 27) 117 ineligible, 61 no attention, and intervention)
27) contact, 17 withdrawn); processing speed
100 enrolled Physical resistance
Attrition: 14 did not training: High
complete, 12 dropped out intensity pneumatic
at f/u resistance machines
targeting most major
muscle groups
Hwang et al. (2012); RCT aMCIa (n = aMCIa waitlist Recruitment: Consecutive Cognitive training: 18 weekly sessions, 2 weeks Verbal memory significantly
South Korea 6) (n = 5) memory clinic outpatients Individualized, 50-minutes each 3 months improved at f/u, other cognitive
(no details given) multicomponent session domains trending towards
Attrition: 2 withdrew program (reality improvement at follow-up
orientation,
computerized
attentional training,
memory training,
visuo-construction
training, executive
function training,
abstract thinking,
homework)
Joosten-Weyn CT MCIa (n = MCIa waitlist Recruitment: 93 enrolled Group-based therapy: 10 weekly sessions, 2 6–8 months
Banningh et al. 47) (n = 40) Attrition: 6 withdrew cognitive behavioral hours each session
(2011); Netherlands therapy principles
with psychoeducation
and memory
rehabilitation, coping
skills

Joosten-Weyn CT Significant Significant Recruitment: 88 recruited See Joosten-Weyn See Joosten-Weyn Intervention end
Banningh et al. others of other waitlist Attrition: 3 withdrew after Banningh et al. (2011) Banningh et al.
(2013); Netherlands MCI patients (n = 27) intake, 1 withdrew after (2011)
(n = 58) intervention
Kurz et al. (2009); CT MCIb (n = MCIb waitlist Recruitment: Consecutive Structured group 22 hours per week Intervention end Verbal and nonverbal memory
Germany 18) (n = 12) enrollment from a program involving for 4 weeks improvements
university psychiatric day- practical problem
clinic solving, self-
Attrition: No information assertiveness training,
stress management,
relaxation training,
journaling, creativity
tasks, cognitive
training (memory
Page 37

aids), and motor/
mobility exercises
Lam et al. (2015); RCT MCIb (n = MCIb Recruitment: 655 Cognitive-Physical 12-month Intervention end Improvement over time on
Hong Kong 132) Social (active) approached at senior training combined: intervention period global cognitive scores, delayed
(n = 131) centers, 100 not eligible, One cognitive activity Three 1-hour memory, and verbal fluency
Chandler et al.
555 enrolled and two mind-body cognitive sessions

Attrition: 132 did not exercises per week
complete Three 1-hour
physical sessions per
week
Law et al. (2014); RCT MCIc (n = MCIc Recruitment: 211 Cognitive therapy: 30 6 sessions for 10 6 months Global cognition, executive
Australia 40) Single blind, screened for eligibility, minutes of weeks function, and memory
occupational 128 excluded, 83 enrolled computerized improvements at f/u
therapy (n = Attrition: 8 did not cognitive training
43) complete, 4 withdrew (visual searching,
prior to 6-month f/u forward-backward
digit recall, and
calculation), 30
minutes of cognitive
strategy training.
Sessions
supplemented with
homework
Reuter et al. (2012); RCT Parkinson’s Random Recruitment: Patients Cognitive training: 1 month intervention 1 month All IGs improved in global
Germany Disease-MCI assignment to approached during an in- Planning, memory, period 6 months cognitive functioning at f/u
Cognitive one of the patient rehabilitation stay decision making, Cognitive training:
training (n = three IGs Attrition: 7 did not concentration, 4× week, 60 minute
72) complete problem solving, and sessions, at least 14
Cognitive summarization, sessions total
training with relaxation and Transfer session: 90
transfer IG occupational training minute sessions, 3×
(n = 75) Cognitive training week, at least 10
Cognitive with transfer: sessions total
training with Cognitive training Motor training: 60
transfer and plus application to minute sessions, 3×
motor everyday tasks of week, 10–12 sessions
training IG cognitive strategies total
(n = 76) and social skills
(transfer).

Additional relaxation
and occupational
training
Cognitive training
with transfer and
motor training: All
elements of cognitive
training with transfer
plus motor
sequencing, dual-
motor tasks, spatial
orientation, walking,
without additional
Page 38

relaxation or
occupational training
Schmitter-Edgecomb RCT MCIa/ MCIa/ Recruitment: 98 dyads Individualized 3-month intervention Intervention end Memory scores improved
and Dyck (2014); Caregiver Caregiver assessed for eligibility, 48 orientation sessions, a period
USA dyads (n = dyads (n = 23) excluded, 55 enrolled half-day “Strategy training
Chandler et al.
23) Standard care: Attrition: 2 dyads did not psychoeducation and problem solving”
“routine complete, 2 dyads workshop, and sessions, 20 sessions
physician withdrew after “strategy training and total, 2 sessions per
visits, intervention completion problem solving” week for 10 weeks, 2
monitoring of but before post-testing group sessions hours per session
disease involving
progression, communication and
active lifestyle social skills training,
maintenance, memory notebooks
and in some skills training, and
cases AChE goal-planning skills
inhibitors and
Namenda”
Tsolaki et al. (2011); RCT MCIa (n = MCIa Recruitment: 751 Cognitive training 5-month intervention Intervention end Global cognitive improvements
Greece 104) Waitlist (n = approached, 575 excluded (attention and period
72) (182 travel restrictions, 8 executive function), 90 minutes per
died, 12 medical problem, cognitive stimulation session, 3 sessions a
321 dementia, 52 on (enhancement of day (1 of each
AChEI), 176 enrolled episodic memory, component), 1
Attrition: No information semantic memory, session per week, 60
autobiographical sessions total (20
memory, mental sessions of each
imagery, and visual component)
memory), and
psychotherapeutic
techniques
(relaxation)

a
Petersen et al., 1999 or 2004;
b
Winblad et al., 2004;

c
Albert et al., 2011;
d
Morris, 1993;
e
Portet et al., 2006.
AChEI = Acetylcholinesterase inhibitor. aMCI = Mild cognitive impairment, amnestic subtype. CG = Control group. CT = Controlled trial. IG = Intervention group. MCI = Mild cognitive impairment. RCT
= Randomized controlled trial.
Intervention: COGPACK® (Marker 2008)

Page 39
Table 6
Everyday Outcomes for Multimodal Intervention Studies

Fiatarone Singh et al. (2014) BADL/−
Chandler et al.
Hwang et al. (2012) KQOL-AD Self-Assessment of

2 weeks f/u/− Cognition*
3 months f/u/− 2 weeks f/u/+
(d = −0.60, 6, 5) 3 months f/u/−
Joosten-Weyn Banningh et al. GDS-15**/− RAND-36-Dutch**/+ IQCODE/+
(2011) (d = 0.20, 63, 30) (d = 0.18, 63, 30)
ICQ-Acceptance subscale**/−
(d = 0.26, 63, 30)
ICQ-Helplessness subscale**/+
(d = 0.20, 63, 30)
Joosten-Weyn Banningh et al. Caregiver Self-report:
(2013) GDS-15/−
ICQ-Acceptance subscale/ −
ICQ-Helplessness subscale/−
IQCODE/−
RAND-36-Dutch Wellbeing
subscale/+
RMBPC hindrance/−
RMBPC frequency/+
SCQ/−
Kurz et al. (2009) BADL/+ BDI-G/+
(d = 0.38, 18, 12) (d = 1.01, 18, 12)
Lam et al. (2015) CDAD/+ CSDD/+ MIC/+
(d = −0.33, 93, 101) (d = 0.05, 93, 101) (d = 1.20, 93, 101)
CDR/−
(d = 0.00, 93, 101)
Law et al. (2014) LIADL/−
6 months f/u/−
(d = 0.73, 39, 32)

Reuter et al. (2012) PDQ-39
Cognitive training/−
Cognitive training with transfer/−
Cognitive training with transfer and motor
training/+
Schmitter-Edgecomb and Dyck ADL-PI***/− GDS-SF/− QOL-AD/− CSE/− Caregiver Self-report:
(2014) (d = 0.23, 22, 19) (d = 0.52, 18, 19) (d = 0.04,18,19) (d = −0.26,18,19) CSE/+
EFPT Bill Paying/+ GDS-SF/−
(d = 0.90, 21, 21) QOL-AD/−
MMAA/+
(d = 0.56, 21, 22)
Page 40

Tsolaki et al. (2011) FRSSD/+
(d = 0.71,104,72)
Note. Measures are provided with + or − to reflect whether it was reported as significantly different in the study. When it was possible to calculate effect size, those numbers are provided next to the relevant
test (effect size, final number of participants treated by that time point, final number of comparison participants by that time point, positive effect sizes reflect greater improvement for treatment group
Chandler et al.
relative to comparison group). Cohen’s d effect size computed as [(posttesttreatment − pretesttreatment) − (posttestcontrol − pretestcontrol)]/(pooled baseline standard deviation of both groups). Outcomes
without an effect size did not provide information necessary to compute standardized mean differences.
*
Study-specific measure.
**
Effect sizes computed as group differences in Cohen’s d for published posttest-pretest changes.
***
Reported by caregiver in reference to the patient.
Measures: ADCS-MCI-ADL (Alzheimer’s Disease Cooperative Study MCI Activities of Daily Living Scale; Galasko et al. 1997); ADL-PI (Activities of Daily Living-Prevention Instrument; Galasko et al.
2006); BADL (Bayer-Activities of Daily Living; Hindmarch et al. 1998); BDI-G (Beck Depression Inventory-German version; Hautzinger et al. 1994); CDAD (Chinese Disability Assessment for Dementia;
Mok et al. 2005); CDR (Clinical Dementia Rating; Morris 1997); CSDD (Cornell Scale for Depression in Dementia; C. Lam et al. 2004); CSE (Coping Self-efficacy Scale; Chesney et al. 2006); EFPT
(Executive Function Performance Test; Baum et al. 2007): FRSSD (Functional Rating Scale of Dementia; Hutton 1990); GDS (Geriatric Depression Scale; Yesavage et al. 1983); GDS-15 (Geriatric
Depression Scale-15 item; Herrmann et al. 1996); GDS-SF (Geriatric Depression Scale-Short form; Sheikh et al. 1986); ICQ (Illness Cognition Questionnaire; Evers et al. 2001); IQCODE (Informant
Questionnaire on Cognitive Decline in the Elderly; De Jonghe et al. 1997); KQOL-AD (Korean Quality of Life-Alzheimer’s Disease; Shin 2006); LIADL (Lawton Instrumental Activities of Daily Living
Scale Hong Kong; Tong and Man 2002); MIC (Memory Inventory for Chinese; Cheong et al. 2006); MMAA (Medication Management Ability Assessment; Patterson et al. 2002); PDQ-39 (Parkinson’s
Disease Questionnaire; Jenkinson et al. 1995); RAND-36-Dutch (Van der Zee and Sanderman 1993); RMBPC (Revised Memory and Behavioral Problems Checklist-Dutch; Teunisse et al. 1997); SCQ
(Sense of Competence Questionnaire; Vernooij-Dassen et al. 1996).

Page 41
Table 7
Summary of Meta-analyses by Intervention Modality and Outcome Type
Publication Bias Statistics
Group k d 95% CI τ2 p(Q) Fail Safe N Begg and Mazumdar’s rank correlation (p-value) V&W 1 V&W 2 V&W 3 V&W 4
Chandler et al.
Intervention Modality
Computer 15 0.31 0.12 – 0.51 0.00 .56 40 .00 (1.00) 0.24 0.13 0.28 0.23
Therapist 57 0.20 0.11 – 0.30 0.04 .43 618 .30 (< .001) 0.12 −0.82 0.17 0.14
Multimodal 19 0.31 0.08 – 0.54 0.19 .69 219 .12 (.48) 0.19 −0.96 0.27 0.23
Outcome Type
Mood 26 0.16 0.03 – 0.28 0.02 .44 74 .26 (.07) 0.09 0.02 0.12 0.11
Metacognition 24 0.37 0.15 – 0.58 0.16 .88 301 .22 (.14) 0.23 −0.88 0.29 0.20
ADL 31 0.32 0.16 – 0.47 0.09 .65 366 .10 (.43) 0.21 −0.90 0.27 0.21
QOL 10 0.06 −0.11 – 0.22 0.00 .44 −9 −.11 (.66) −0.00 −0.54 0.04 0.03
Note. k = number of outcomes included in this category; individual studies could contribute multiple outcomes; see Table 7 for classification of, and specific outcomes contributed by, each study; d =
standardized mean difference in improvement for treatment minus comparison group. Positive values indicate greater improvement in the treatment group; 95% CI = estimated 95% confidence interval of
the standardized mean difference; τ2 = tau squared, a random effects estimate of the between-outcome heterogeneity in effect size, with larger values representing greater heterogeneity; p(Q) = probability
associated with a random effects test of the null hypothesis of homogeneity, with non-significant values (p > .05) suggesting that we cannot reject the null hypothesis of homogeneous effect sizes among
studies in this intervention modality; Rosenthal’s (1979) Fail Safe N is the estimated number of studies that would need to exist to turn a significant population effect size estimate into a non-significant one;
strong/significant Begg & Mazumdar’s (1994) correlation coefficients are indicative of greater bias; V&W: Vevea and Woods (2005) adjusted effect size estimates under four conditions: 1 = Moderate one-
tailed selection, 2 = Severe one-tailed selection, 3 = Moderate two-tailed selection, and 4 = Severe two-tailed selection. All publication bias statistics were estimated under random effects models.

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Everyday Impact of Cognitive Interventions in Mild Cognitive

systematic review; meta-analysis

Contact: M. J. Chandler, chandler.melanie@mayo.edu.

characterized by 1) a cognitive concern, 2) cognitive impairment on psychometric testing, 3)

Neuropsychol Rev. Author manuscript; available in PMC 2017 September 08.

Most recently, when performing a systematic review of all types of nonpharmacological

Neuropsychol Rev. Author manuscript; available in PMC 2017 September 08.

restitution), therapist-based interventions (where the goal is most often cognitive

Inclusion and Exclusion of Publications

Neuropsychol Rev. Author manuscript; available in PMC 2017 September 08.

Extraction of Data from Articles

Neuropsychol Rev. Author manuscript; available in PMC 2017 September 08.

Computerized Interventions Overview

Neuropsychol Rev. Author manuscript; available in PMC 2017 September 08.

Sample sizes ranged from 8 to 51 (M = 21.3, SD = 15.2) and 7 to 49 (M = 17.7, SD = 14.7)

Therapist-Based Interventions Overview

Neuropsychol Rev. Author manuscript; available in PMC 2017 September 08.

Multimodal Interventions Overview

randomly assigned to incremental levels of intervention (N = 223). MCI patient multi-modal

Neuropsychol Rev. Author manuscript; available in PMC 2017 September 08.

Variation in Effect Sizes by Treatment Modality and Outcome Type—Two tests

Neuropsychol Rev. Author manuscript; available in PMC 2017 September 08.

The second comparison of subgroup differences examined differences between outcome

We examined stem-and-leaf plots broken down by the intervention approach, and by

category by intervention approach (e.g., mood outcomes by computerized intervention), the

Computerized Interventions Outcomes

Neuropsychol Rev. Author manuscript; available in PMC 2017 September 08.

found no impact of training on this scale.

Metacognitive: In four different studies, participants used five different instruments to

Therapist-Based Interventions Outcomes

Neuropsychol Rev. Author manuscript; available in PMC 2017 September 08.

Multimodal Interventions Outcomes

Metacognition: Metacognitive outcomes were assessed in four of the 10 studies with

Neuropsychol Rev. Author manuscript; available in PMC 2017 September 08.

computerized plus non-computerized cognitive intervention on a self-assessment of

Neuropsychol Rev. Author manuscript; available in PMC 2017 September 08.

Computerized interventions tend to be more restitution based, focus more on post-training

Neuropsychol Rev. Author manuscript; available in PMC 2017 September 08.

Neuropsychol Rev. Author manuscript; available in PMC 2017 September 08.

Neuropsychol Rev. Author manuscript; available in PMC 2017 September 08.

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