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CRITICAL REVIEW
The Neuropsychological Profile of Mild Cognitive Impairment
in Lewy Body Dementias
Joanna Ciafone1, Bethany Little1, Alan J. Thomas1and Peter Gallagher1,2
1Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom
2Northern Centre for Mood Disorders, Newcastle University, Newcastle upon Tyne, United Kingdom
(RECEIVED March 20, 2019; FINAL REVISION July 5, 2019; ACCEPTED August 21, 2019; FIRST PUBLISHED ONLINE December 12, 2019)
Abstract
Objective: Dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD) have substantial clinical and
biological overlap, with cognitive deficits typically observed in the executive and visuospatial domains. However, the
neuropsychological profiles of mild cognitive impairment (MCI) associated with these disorders are not well understood.
Methods: This systematic review examined existing literature on cognition in MCI due to LB disease (MCI-LB) and
PD (PD-MCI) using an electronic search of seven databases (Medline, Embase, Psychinfo, PubMed, ProQuest, Scopus,
and ScienceDirect). MCI-LB results were reviewed narratively given the small number of resulting papers (n=7).
Outcome variables from PD-MCI studies (n=13) were extracted for meta-analysis of standardised mean differences
(SMD). Results: In MCI-LB, executive dysfunction and slowed processing speed were the most prominent
impairments, while visuospatial and working memory (WM) functions were also poor. MCI-LB scored significantly
lower on verbal memory tests relative to controls, but significantly higher than patients with MCI due to Alzheimer’s
disease. Quantitative analysis of studies in PD-MCI showed a similar profile of impairment, with the largest deficits in
visuospatial function (Benton Judgement of Line Orientation, SMD g=−2.09), executive function (Trail Making Test
B, SMD g=−1.65), verbal ability (Naming Tests, SMD g=−0.140), and WM (Trail Making Test A, SMD g=−1.20).
In both MCI-LB and PD-MCI, verbal and visuospatial memory retrieval was impaired, while encoding and storage
appeared relatively intact. Conclusion: The findings of this systematic review indicate similar neuropsychological
profiles in the MCI stages of DLB and PDD. Executive impairment may at least partially explain poor performance in
other domains.
Keywords: Dementia with Lewy bodies, Parkinson’s disease dementia, Cognition, Visuospatial working memory, Verbal
learning and memory, Executive function
INTRODUCTION
The construct of mild cognitive impairment (MCI) encapsu-
lates the intermediatestage between normal ageing and demen-
tia in which cognitive decline is present yet activities of daily
living are preserved (Albert et al., 2011; Flicker, Ferris, &
Reisberg, 1991; Petersen et al., 1999). Development of the
concept of MCI has supported a proliferation of studies of
the prodromal stages of dementia, but most of the focus has
been in MCI later diagnosed as Alzheimer’sdisease
(MCI-AD). Less work has been devoted to prodromal demen-
tia with Lewy bodies (DLB),the second mostcommon form of
neurodegenerative dementia (Donaghy & McKeith, 2014).
MCI-LB refers to MCI in individuals who will eventually be
characterised as DLB, although DLB may have other prodro-
mal presentations, such as rapid eye movement sleep behav-
iour disorder (RBD). While DLB is diagnosed when dementia
precedes or accompanies parkinsonism (with the latter not
necessarily occurring), another Lewy body dementia (LBD),
Parkinson’s disease dementia (PDD), is defined as dementia
occurring in the context of existing PD. The differentiation
between DLB and PDD is operationalised by a “one year rule”,
so that PDD is diagnosed when PD occurs a year or more before
dementia. LBDs share neuropathological hallmarks (Lewy
bodies and Lewy neurites; Aarsland, 2016; Boeve, 2012;
Braak et al., 2003) and appreciable overlap in clinical presen-
tation, including neuropsychiatric symptoms, autonomic
Correspondence and reprint requests to: Joanna Ciafone, Institute of
Neuroscience, Newcastle University, Biomedical Research Building, 3rd
Floor, Campus for Ageing and Vitality, Newcastle upon Tyne NE4 5PL,
United Kingdom. E-mail: joanna.ciafone@newcastle.ac.uk
Journal of the International Neuropsychological Society (2020), 26, 210–225
Copyright © INS. Published by Cambridge University Press, 2019.
doi:10.1017/S1355617719001103
210
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features such as constipation and orthostatic dizziness, sleep
disturbances, and response to cholinergic therapy (Burn &
McKeith, 2003; Donaghy, O’Brien, & Thomas, 2015; Thomas
et al., 2006). Indeed, the DLB/PDD Working Group has
suggested that “there is no clinical symptom that absolutely
distinguishes DLB and PDD”(Lippa et al., 2007, p. 817).
Cohort studies suggest neuropsychological impairment in
PD is not solely a late-stage issue, with subtle deficits detect-
able up to 7 years before diagnosis (Darweesh et al., 2017).
Because cognitive impairment may not always be detected or
reported at presentation (Aarsland et al., 2008; reviewed in
Goldman, Williams-Gray, Barker, Duda and Galvin, 2014),
many patients with an early alpha-synucleinopathy may be
labelled as PD-MCI once parkinsonism advances, and PDD
if loss of autonomy occurs, despite longer-standing cognitive
deficits. Indeed, updated PD diagnostic criteria state that
dementia at the time of parkinsonism onset is not an exclud-
ing factor for diagnosis (Postuma et al., 2015). Therefore, a
PD-MCI diagnosis may also capture prodromal DLB and
much existing work in PD-MCI may include prodromal
DLB patients (Fujishiro, Nakamura, Sato, & Iseki, 2015;
Massa et al., 2019). Massa et al. (2019), in recognition of
the relevance of this diagnostic issue, recently reported on
a small case series of patients that presented first with cogni-
tive impairment and later developed motor symptoms consis-
tent with PD (mean time to PD diagnosis =2.9 years, range
0.5–6.1), with nearly 50% having converted to dementia at
follow-up. Massa et al. (2019) note that these patients meet
both prodromal DLB (McKeith et al., 2017) and PD with cog-
nitive presentation (Postuma et al., 2015) criteria. Moreover,
utilising neuroimaging data, they conclude that, “the distinc-
tion between prodromal DLB and PD with a cognitive presen-
tation seems blurry at the pathophysiological level, and these
patients might be labelled as affected with prodromal LBD, as
suggested by some authors (Donaghy & McKeith, 2014;
McKeith, 2016)”(Massa et al., 2019, p. 14).
As such, a review of the neuropsychological profile of
MCI-LB should be informed by current research in cognition
in PD-MCI. In terms of neuropsychological presentation,
PDD and DLB may be indistinguishable when advanced, with
cognitive deficits typically observed in the executive function
(EF), visuospatial and memory domains (Aarsland, 2016).
However, some differences between LBD groups have been
reported, with DLB performing more poorly than PDD in tasks
requiring EF and attentional ability (Downes et al., 1998;
Gnanalingham, Byrne, Thornton, Sambrook, & Bannister,
1997; Mondon et al., 2007). The current systematic review aims
to evaluate existing research on cognition in MCI-LB and
PD-MCI.
METHODS
Search Strategy and Scope
The present review examined studies that used standardised tests
of domain-level cognitive impairment in MCI associated with
Lewy body disease. Key terms of the search (updated January
2019) of seven databases (Medline, Embase, Psychinfo,
PubMed, ProQuest, Scopus, ScienceDirect) were chosen to
target the three defining aspects of the studies of interest:
(1) patients with clinical symptoms consistent with Lewy body
neuropathology (“Lewy bodies,”), (2) patients in a predementia
stage (“MCI”), and (3) the use of neuropsychological methods
(“neuropsychology”). Synonyms were created for each term
and exploded with medical subject headings. Results were
limited to human studies in peer-reviewed English language
journals excluding reviews, meta-analyses, abstracts, case stud-
ies, commentaries, discussion papers, editorials, and confer-
ence proceedings. Articles that were primarily imaging or
eye-tracking studies were removed. Titles and abstracts were
reviewed independently by two authors (JC, BL) and discrepan-
cies were discussed to achieve consensus.
Inclusion and Exclusion Criteria
Included studies measured at least one cognitive domain with an
established neuropsychological task (previously published in
≥10 peer-reviewed journal articles). Composite scores of stand-
ardised tasks were accepted. Exclusion criteria were: unclear,
insufficient, or non-clinical PD diagnostic criteria; unspecified
MCI classification; n<10 per group; use of global measures
[e.g. Mini-Mental State Exam (MMSE)]; domain-level
composite data only; or no healthy controls (HCs). Where studies
included a third comparison group, patient and HC data were
extracted. Baseline data were extracted from longitudinal studies.
Data Review, Extraction, and Synthesis
The following variables for each cognitive outcome measure
were extracted: first author, year of publication, country of pub-
lication, participant numbers, participant age means and standard
deviations (SD), PD diagnostic criteria, MCI criteria, disease
duration, and outcome measure means, SDsandp-values. The
direction of effect sizes (ES) was reversed as appropriate to
reflect deficits as negative ES. Bias-corrected ES Hedges’g
(Hedges & Olkin, 1985) and 95% confidence interval (CI) based
on the pooled estimate of SD were calculated and plotted by cog-
nitive domain. For commonly reported tasks, summary ES and
95% total CIs were calculated using Cochrane Reviews’Review
Manager (RevMan; The Nordic Cochrane Centre, 2014)fixed
effect model and inverse variance. Due to different testing param-
eters and scoring across studies (i.e. z-scores), the summary ES
were calculated as the standardised mean difference (SMD) to
avoid overestimation of the overall difference (Hedges’adjusted
g; Deeks & Higgins, 2010).
RESULTS
The Evidence Base
The database search resulted in >7000 articles; 6286 after
removing duplicates. Initial title review yielded 713 referen-
ces that were screened by abstract. Articles were typically
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removed for topic irrelevance, especially not targeting early
Lewy body disorders, only measuring cognition globally, or
being primarily an imaging study. The full text of the remain-
ing 73 articles was reviewed by both reviewers and any ambi-
guity discussed for consensus. Reasons for removal at full-text
screen were: absence of HCs (n=7), unclear or insufficient PD
diagnosis (n=11), irrelevant patient (n=10) or control (n=9)
groups, inappropriate cognitive tasks (n=5), ≤10 participants
tested (n=2), being primarily an imaging study (n=1), and
cohort redundancy with other retained papers (n=8; the paper
providing the most comprehensive cognitive task data was
chosen). Studies excluded for absences of HCs (n=7) gener-
ally compared PD-MCI with PD with normal cognition
(PD-NC) or normative data. They were reviewed informally
for relevancy (see supplementary table).
MCI-LB Results
Table 1displays details of retained papers. The search strat-
egy yielded only one study in MCI-LB that met full inclusion
criteria (Kemp et al., 2017). Six studies measured cognition in
MCI-LB, but did not use a HC group. One paper had only
nine patient subjects (Jicha et al., 2010). Given the small
number and heterogeneity of MCI-LB results, these papers
were retained for narrative review.
Kemp et al. (2017), the only paper meeting full inclusion
criteria, considers neuropsychological scores as well as social
cognitive ability. Patients are classified as “prodromal DLB”
(n=37) for meeting MCI criteria (Petersen, 2004) and having
at least two core symptoms of DLB (McKeith et al., 2005).
After adjusting for age, sex, and education level, prodromal
DLB scored significantly lower than HCs (n=29) on 14 of
21 extracted outcome measures, representing EF, attention
and processing speed, working memory (WM), visuospatial
memory, visuoconstructive ability, and verbal memory.
The largest ES were reported on semantic verbal fluency
(EF; g=−1.65) and digit symbol substitution (attention/
processing speed, g=−1.16) tasks. The other significant
ES were in the g=−0.53 to −0.93 range. Prodromal DLB
showed impaired immediate and delayed free recall relative
to controls. However, the authors suggested intact “real ver-
bal memory (i.e. storage)”in the majority of their patients
(29 of 37; outcome measure not specified) and emphasised
retrieval deficits as related to executive impairments
(Kemp et al., 2017). Kemp et al. (2017) also concluded that
verbal memory (free and cued selective reminding test total
recall and recognition, g=−0.60) was better preserved than
visual recognition memory [Delayed Matching to Sample-48
Items (g=−0.79)] in their sample.
All studies in MCI-LB used clinical diagnostic criteria
except for Jicha et al. (2010), where neuropathological diagno-
ses were utilised. No significant differences between
MCI-LB and MCI-AD in global cognitive measures (e.g.
MMSE) were reported. Excluding Kemp et al. (2017), 28 of
the remaining 79 (35.44%) extracted outcome variables
showed differential performance between MCI-LB and
MCI-AD after bias correction (see description in Table 1
and individual statistics in the supplementary materials).
This tally does not include individual tasks removed that did
not meet a priori exclusion criteria for publication in at least
10 peer-reviewed journals. Twenty-one variables showed
poorer performance by MCI-LB relative to MCI-AD in visuo-
spatial, attention, and psychomotor speed. Both Bussè et al.
(2018) and Cagnin et al. (2015) reported poorer performance
in MCI-LB in WM, visuospatial and visuoconstructive ability,
and EF, with magnitudes ranging from medium (g=−0.56,
Object Decision Visuospatial Test, Cagninet al., 2015)tolarge
(g=−0.95, Digit Span Backwards, Cagnin et al., 2015)and
very large (g=−3.45, Pentagon Test number of angles,
Busse, Hensel, Gühne, Angermeyer, & Riedel-Heller,
2006). Donaghy et al. (2018) showed deficits in MCI-LB rel-
ative to MCI-AD of medium ES in attention (Digit Vigilance,
g=−0.56), EF (difference between Choice and Simple
Reaction Time, g=−0.53), and visuospatial function
(Angle Task, g=−0.55). Sadiq et al. (2017) reported impaired
scores on EF (letter fluency, g=−0.62) and attention (Trails B,
g=−0.51), while Yoon, Kim, Moon, Yong and Hong (2015)
only showed impairment inEF (g=−0.72; Stroop Colour test)
and there were no significant differences in Jicha et al. (2010)
after bias correction. MCI-LBs performed significantly better
than MCI-AD on verbal memory outcome measures (immedi-
ate recall, delayed recall, and recognition) in three studies
(Bussè et al., 2018; Cagnin et al., 2015;Yoonetal.,2015)with
generally large ES (g=0.66–3.80, mean g=1.82).
The studies showing deficits in MCI-LB in the domains of
WM and attention, EF and visuospatial function were not
wholly consistent, as some outcome variables in the same
domains did not reach significance. For example, Donaghy
et al. (2018) reported significant differences in only one of
the nine outcome measures of attention and psychomotor
speed (Digit Vigilance).
Additionally, both Yoon et al.(2015)andSadiqetal.(2017)
also compared MCI-LB/DLB-MCI to an MCI-stable group at
follow-up. In Yoon et al. (2015; 5 years of follow-up), MCI-LB
was impaired in the domains of visuospatial ability and
memory [Rey–Osterrieth Complex Figure (ROCF) recognition
and copy], EF (Stroop Colour, verbal semantic fluencies),
WM/attention (Digit Span Forwards and Backwards), and ver-
bal learning and memory (Seoul Verbal Learning Test delayed
recall) relative to MCI that did not convert to dementia. Sadiq
et al. (2017; mean follow-up 2.8 years) found that DLB-MCI
patients are also impaired in EF (letter fluency) and visuocon-
struction (clock drawing test) relative to stable-MCI.
PD-MCI Evidence Base
Demographic and clinical characteristics of
participants
Details of quantitatively reviewed articles are summarised in
Table 1and group characteristics are summarised in Table 2.
Some studies did not provide details of age (but were
age-matched) or disease duration. For PD diagnosis, studies
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Table 1. Details of all included studies (MCI-LB and PD-MCI)
First author
(year) Country
Patient group
Comparison
group
Design MCI criteria Diagnostic criteria
Disease
duration
(months)
Mean (SD)
Domains
measured
Outcome
measures
impairedType nType n
Bussè (2018) Italy Prodromal
DLB
19 Prodromal
AD
25 Cross-sectional with
diagnosis after at
least 3 years of
follow-up.
Petersen (2004) McKeith et al.
(2017), “DLB
Possible”.
–EF 2 of 3
WM/att 2 of 3
Verbal 0 of 7
Visuospatial 4 of 5
Cagnin (2015) Italy MCI-LB 25 MCI-AD 28 Retrospective analysis
of records at first
(predementia) visit.
Absence of dementia
(MMSE >26) and
“functional impairment in
everyday life”. Exclusion:
inability to establish a
definite diagnosis at
follow-up and cognitive
decline due to
comorbidities.
McKeith et al.
(2005)
–EF 2 of 2
WM/att 1 of 2
Verbal 0 of 2
Visuospatial 4 of 10
Donaghy (2018) UK MCI-LB 41 MCI-AD 24 Cross-sectional. Albert et al. (2011) McKeith et al.
(2017), “DLB
Probable”.
–EF 1 of 1
WM/att 1 of 9
Verbal 0 of 3
Visuospatial 1 of 1
Jicha (2010) USA MCI-LB 9 MCI-AD 12 Retrospective analysis
of records of
neuropathically
determined groups.
Records reviewed for MCI
criteria of 2nd International
Consensus Panel on MCI,
Stockholm, Sweden
(Winblad et al., 2004)
including impairment of at
least 1.5 SDs below age
and education matched
controls on “formal
testing”(p. 1807).
Neocortical DLB
(below Braak
stage IV) with no
significant AD
pathology or
vascular disease),
–EF 0 of 3
WM/att 0 of 2
Verbal 0 of 3
Kemp (2017) France Prodromal
DLB
37 HCs 29 Cross-sectional. Petersen (2004) McKeith et al.
(2005), “DLB
Probable”.
–EF 4 of 4
WM/att 2 of 4
Verbal 3 of 3
Visuospatial 5 of 9
Sadiq (2017) UK DLB-MCI 21 AD-MCI 107 Retrospective,
unselected
sample.
Petersen et al. (1997) McKeith et al.
(2005), “DLB
Probable”.
21.6 (13.2) EF 1 of 2
WM/att 1 of 2
Verbal 0 of 2
Visuospatial 0 of 1
(Continued)
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Table 1. (Continued )
First author
(year) Country
Patient group
Comparison
group
Design MCI criteria Diagnostic criteria
Disease
duration
(months)
Mean (SD)
Domains
measured
Outcome
measures
impairedType nType n
Yoon (2015) South
Korea
MCI-LB 18 MCI-AD 45 Prospective
cohort.
With regard to matched
controls: (1) scores below
16th percentile in at least
one of five cognitive
domains on the Seoul
Neuropsychological
Screening Battery (Yang,
2003), (2) scores above the
16th percentile on Korean
MMSE, and (3) no
impairments in Activities
of Daily Living.
McKeith et al.
(2005)
–EF 1 of 5
WM/att 0 of 2
Verbal 0 of 6
Visuospatial 0 of 4
Anderson
(2013)
UK PD-MCI 19 HC 16 Matched on age Score of 93 or less on
Addenbrooke’s Cognitive
Examination-Revised, no
lower score limit
(Komadina, 2011)
Calne et al. (1992) Not given EF 3 of 4
Biundo (2014) Italy PD-MCI 49 HC 18 Adjusted normative
data: age, education
MDS level II criteria (Litvan
et al., 2012)
UKPDS (no
reference)
109.7 (72.0) EF 2 of 3
WM/att 1 of 4
Verbal all
Visuospatial all
Bocanegra
(2015)
Colombia PD-MCI 17 HC 17 Matched on age,
education, sex
MDS level I criteria (Litvan
et al., 2012)
UKPDS (Hughes
et al., 1992)
Not given Verbal all
Costa (2015) Italy PD-MCI 48 HC 20 Groups not matched MDS level II criteria (Litvan
et al., 2012)
UKPDS (Hughes
et al., 1992)
75.6 (49.2) EF all
WM/att 1 of 5
Verbal all
Visuospatial all
Dalrymple-
Alford (2011)
New
Zealand
PD-MCI 3 HC 34 Adjusted (z-scores):
age, education
Neuropsychological scores
1.5–2 SDs below
normative data in one
domain.
UKPDS (Hughes
et al., 1992)
Not given EF all
WM/att all
Verbal all
Visuospatial all
Galtier (2016) Spain PD-MCI 26 HC 20 Matched on age,
education, intelligence,
manual preference, sex
MDS level II criteria (Litvan
et al., 2012)
UKPDS (Hughes
et al., 1992)
105.7 (67.2) EF 2 of 4
WM/att 0 of 1
Verbal 3 of 4
Visuospatial all
(Continued)
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Table 1. (Continued )
First author
(year) Country
Patient group
Comparison
group
Design MCI criteria Diagnostic criteria
Disease
duration
(months)
Mean (SD)
Domains
measured
Outcome
measures
impairedType nType n
Hessen (2016) Norway PD-MCI 13 HC 25 Groups not matched Clinical and
neuropsychological
criteria (National Institute
on Aging –Alzheimer’s
Association). At least one
of the six
neuropsychological
subtests impaired (1.5 SD
or more below normative
scores)
UKPDS (Berardelli
et al., 2013)
25.2 (9.6) EF all
Verbal all
Peraza (2017) UK PD-MCI 37 HC 30 Groups not matched MDS level II criteria (Litvan
et al., 2012)
UKPDS (Hughes
et al., 2002)
5.81 (4.51) EF all
WM/att all
Poletti (2012) Italy PD-MCI 18 HC 100 Matched on age MDS level II criteria (Litvan
et al., 2012)
UKPDS (Hughes
et al., 1992)
11.0 (8.8) EF 7 of 8
WM/att all
Verbal all
Visuospatial all
Sanyal (2014) India PD-MCI 90 HC 280 Matched on age, sex Clinical Criteria. UKPDS
(Conditions,
2006)
34.8 (55.2) EF all
Verbal all
Visuospatial 1 of 2
Song (2008) Korea PD-MCI 20 HC 33 Groups not matched Neuropsychological scores of
at least 2 SD below control
group in at least one test.
UKPDS (Hughes
et al., 1992)
57.6 (29.9) EF all
WM/att 1 of 2
Verbal 2 of 4
Visuospatial 1 of 4
Wang (2015) China PD-MCI 96 HC 163 Matched on age,
gender, education
MDS level II criteria (Litvan
et al., 2012)
UKPDS (Hughes
et al., 1992)
61.2 (41.0) EF all
WM/att all
Verbal 3 of 4
Visuospatial all
Yu (2012) Taiwan PD-MCI 94 HC 84 Matched on age,
education, sex
Neuropsychological scores of
at least 1.5 SD below
normative mean (or below
the fifth percentile) of
normative samples in at
least one domain. Unclear
when norms of HC scores
were used.
UKPDS (Hughes
et al., 1992)
52.9 (27.1) EF all
WM/att 6 of 7
Verbal all
Visuospatial all
MCI =mild cognitive impairment; DLB =dementia with Lewy bodies; AD =Alzheimer’s disease; PD =Parkinson’s disease; HC =healthy controls; MMSE =Mini-Mental State Examination; UKPDS =UK Parkinson’s
Disease Society; MDS =Movement Disorder Society; SD =standard deviation; EF =executive function; WM/att =working memory/attention.
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cited United Kingdom PD Society Brain Bank criteria
(UKPDS; Hughes, Daniel, Kilford, & Lees, 1992) or equiv-
alent, and National Institute of Neurological Disorders and
Stroke criteria (Gelb et al., 1999). To define PD-MCI, seven
studies used MDS criteria (Litvan et al., 2012). The remaining
studies used a mix of clinical and neuropsychological diag-
nostic criteria, including both normative and control data
as impairment criteria.
Exclusion of tasks
Unclear task information or use of unestablished tasks
(<10 published peer-reviewed references) necessitated the
removal of variables from 8 of 13 studies. While not leading
to removal from analyses, details provided were often also insuf-
ficient regarding the length of delay in memory tasks. Only the
two most commonly reported measures per task and paper were
retained in order to focus synthesis and avoid redundancy (e.g.
for card sorting tasks, “categories achieved”and “perseverative
errors”were used). Similarly, closely related variables adminis-
tered for more experimental rationales were removed to avoid
redundancy (e.g. from Costa et al. (2015), “Drawings Copy”
was extracted while “Drawings with Landmarks Copy”was
not). Sums were not extracted if separate scores were also
provided, for example, with Digit Span Total (Yu et al., 2012).
Domain-Level Cognitive Assessments
Outcome measures were organised into the domains of WM,
EF, visuospatial, and verbal function, corresponding to their
face validity. This conflicted with a number of papers that
assigned outcome measures to domains of which they were
not the primary target. For example, verbal fluency tasks were
referred to as language or memory tasks in five papers when
they are most commonly accepted as measures of EF
(MacCarthy, 1972). Overall, every study showed worse
performance in patients than HCs in at least one cognitive
domain. Table 2displays the number of outcome variables
retained in each domain for each group, after removal
described above, and how many were impaired. Table 3
displays summary ES of frequently reported outcome varia-
bles. See supplementary materials for individual ES and CI,
and for figures displaying data not included below. Across
domains, there was a pattern of smaller ES reported by studies
with larger sample sizes.
Executive function, working memory, and attention
A variety of EF and WM tasks were used, with ES ranging
from moderate (g=−0.45; Yu et al., 2012, semantic fluency)
to very large (g=−2.47; Sanyal, Banerjee, & Rao, 2014;
semantic fluency). EF was the most frequently targeted
Table 2. Summary of impairments in PD-MCI from retained paper (n=13) across neuropsychological domains
PD-MCI group Control group
n
Age
Mean (SD) n
Age
Mean (SD) Domain
Proportion of studies with at least one
impaired variable relative to controls
Proportion of outcome variables
impaired relative to controls
530 63.8 (8.3) 840 61.7 (9.3) Executive function 100% (13/13) 89% (39/44)
WM/Attention 88.9% (8/9) 68% (21/31)
Visuospatial L&M 88.9% (8/9) 91% (30/33)
Visuospatial WM 75.0% (3/4) 67% (4/6)
Verbal L&M 100% (11/11) 88% (30/34)
MCI-LB group Control group
Domain
Proportion of studies with at least one
impaired variable relative to controls
Proportion of outcome variables
impaired relative to controlsn
Age
Mean (SD) n
Age
Mean (SD)
37 67.2 (8.6) 29 68.8 (7.9) Executive function 100.0% (1/1) 100.0% (4/4)
WM/Attention 100.0% (1/1) 50.0% (2/4)
Visuospatial L&M 100.0% (1/1) 55.6% (5/9)
Visuospatial WM ––
Verbal L&M 100.0% (1/1) 100.0% (3/3)
MCI-LB group MCI-AD group
Domain
Proportion of studies with at least one
impaired variable relative to controls
Proportion of outcome
variables impaired relative to
controlsn
Age
Mean (SD) n
Age
Mean (SD)
133 76.0 (7.92) 241 75.0 (8.0) Executive function 83.3% (5/6) 43.8% (7/16)
WM/Attention 67.0% (4/6) 25.0% (5/20)
Visuospatial L&M 60.0% (3/5) 42.9% (9/21)
Visuospatial WM 100.0% (1/1) 100.0% (1/1)
Verbal L&M 0.0% (0/6) 0.0% (0/20)
SD =standard deviation; PD =Parkinson’s Disease; MCI =mild cognitive impairment; WM =working memory, L&M =learning and memory.
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domain. Commonly reported outcome measures were from
card sorting, verbal fluency, and Stroop tasks, with patients
showing summary impairments in the medium (g=−0.63)
to large (g=−1.30) range (Table 3). Verbal fluency tasks,
commonly used measures of EF (Baddeley, 1996), can be
separated into semantic and phonemic fluency paradigms.
Both showed large ES (Figure 1a and 1b), but PD-MCI
was somewhat more impaired in semantic fluency tasks.
PD-MCI showed a lower proportion of only 21 of 30
impaired WM variables, but with a similar range in summary
ES (g=−0.52 to −1.65) as in EF. Six studies included WM
measures that in particular require psychomotor speed, including
Trails A and B. While both summary ES are large, there was
greater impairment on Trails B, which requires EFs, than
Trails A. All four studies that used Trails B reported significant
and large deficits (above 1 SD), with a SMD of g=−1.65
(−1.93, −1.37). A similar divergence was observed between
Digit Span Forwards (g=−0.52) and Backwards (g=−0.69).
Visuospatial domain
Patients performed significantly worse than controls on 30 of
the 33 visuospatial memory variables. The largest SMD com-
puted from the evidence base overall was in judgement of line
orientation (JOLO) (g=−2.09; Benton, Hamsher, Varney, &
Spreen, 1983), making visuospatial function the most frequently
Table 3. Results of tests for commonly reported outcome measures for PD-MCI participants
Domain Outcome measure Studies
Patient
n
Control
n
Std. Mean Difference
(95% CI)
Test for overall
effect Heterogeneity
EF Card sorting –categories
achieved
4 136 224 −1.30 (−1.55, −1.04) z=9.93
(p<.001)
Chi² =3.36, df =3
(p=.34); I² =11%
Card sorting –perseverative
errors
4 110 204 −0.63 (−0.89, −0.37) z=4.72
(p<.001)
Chi² =0.07, df =2
(p=.97); I² =0%
Phonemic fluency 6 267 384 −0.85 (−1.02, −0.67) z=9.48
(p<.001)
Chi² =9.58, df =5
(p=.09); I² =48%
Semantic fluency 8 379 748 −1.07 (−1.21, −0.93) z=14.90
(p<.001)
Chi² =131.77, df =7
(p<.001); I² =95%
Stroop interference
condition
3 127 288 −0.73 (−0.95, −0.51) z=6.54
(p<.001)
Chi² =3.81, df =2
(p=.15); I² =48%
TMT B 4 151 188 −1.65 (−1.93, −1.37) z=11.51
(p<.001)
Chi² =7.74, df =3
(p=.05); I² =61%
WM Digit span forwards 5 257 318 −0.69 (−0.87, −0.51) z=7.47
(p<.001)
Chi² =32.25, df =4
(p<.001); I² =88%
Digit span backwards 5 234 320 −0.52 (−0.70, −0.35) z=5.78
(p<.001)
Chi² =7.99, df =4
(p=.09); I² =50%
TMT A 5 195 272 −1.20 (−1.42, −0.98) z=10.67
(p<.001)
Chi² =20.33, df =4
(p<.001); I² =80%
Verbal Naming tasks 6 220 468 −1.40 (−1.59, −1.21) z=14.50
(p<.001)
Chi² =36.80, df =5
(p<.001); I² =86%
Word list (immediate free
recall)
5 195 341 −0.96 (−1.15, −0.76) z=9.53
(p<.001)
Chi² =28.61, df =4
(p<.001); I² =86%
Word list (delayed free
recall)
7 257 411 −1.25 (−1.43, −1.08) z=13.80
(p<.001)
Chi² =9.31, df =6
(p=.16); I² =36%
Word list (recognition) 3 142 216 −0.07 (−0.29, 0.14) z=0.69
(p=.49)
Chi² =0.39, df =2
(p=.82); I² =0%
Word list (similarities) 3 189 265 −0.50 (−0.70, −0.30) z=4.97
(p<.001)
Chi² =3.44, df =2
(p=.18); I² =42%
VS Benton JOLO 4 176 333 −2.09 (−2.33, −1.85) z=17.28
(p<.001)
Chi² =56.06, df =3
(p<.001)); I² =95%
Figure copy 4 283 481 −1.56 (−1.74, −1.38) z=16.68
(p=.003)
Chi² =153.64, df =3
(p=.18); I² =98%
Drawing –immediate recall 4 130 237 −0.94 (−1.19, −0.70) z=7.57
(p<.001)
Chi² =13.28, df =3
(p=.004); I² =77%
Drawing –delayed recall 7 305 585 −1.03 (−1.19, −0.87) z=12.79
(p<.001)
Chi² =25.83, df =6
(p<.001); I² =77%
ROCF 6 231 258 −1.42 (−1.65, −1.19) z=12.24
(p<.001)
Chi² =93.53, df =5
(p<.001); I² =95%
PD =Parkinson’s disease; MCI =mild cognitive impairment; EF =executive function; WM =working memory; VS =visuospatial; TMT =Trail Making Test;
JOLO =judgement of line orientation; ROCF =Rey–Osterrieth complex figure.
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and severely impaired domain. Only Song, Kim, Jeong, Song
and Lee (2008) reported a lack of difference in visuospatial
function (ROCF copy, immediate and delayed recall). Figure
copying and recall was a common visuospatial paradigm, but
recall conditions varied substantially in the length of delay.
Summary ES for the PD-MCI group showed more pronounced
deficits in figure copying than in either immediate or delayed
recall. Song et al. (2008) also tested delayed figure recognition
and found a moderate deficit in PD-MCI relative to controls
(g=−0.60). However, potential outliers (Poletti et al., 2012;
Sanyal et al., 2014) complicate interpretation (Figure 2).
Six outcomes from four studies targeted the visuospatial
component of WM, per fractionated models proposed by
Baddeley and Hitch (1974), Logie and Pearson (1997),
and others. These include the Corsi Test (Corsi, 1972)
and Pattern Recognition Memory (Robbins et al., 1998).
A summary ES computed from Corsi Tests administered
byPolettietal.(2012), Costa et al. (2015), and Biundo
et al. (2014) suggested a moderate impairment in PD-
MCI relative to controls, with Poletti et al. (2012)having
the only significant finding.
Verbal domain
Patients performed significantly worse than controls in 30 out
of 34 of the verbal domain variables. Each study that tested
Fig. 1. Bias-corrected effect sizes of (a) phonemic verbal fluency scores and (b) semantic verbal fluency scores in PD-MCI relative to controls
in individual studies (circles) and as a summary effect size by group (diamonds).
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verbal learning and memory reported at least one significant
difference between groups. However, three studies measur-
ing verbal learning and memory did not find a significant
difference between groups: California Verbal Learning
Test in Galtier, Nieto, Lorenzo and Barroso (2016), Hopkins
Verbal Learning Test (HVLT) and Boston Naming Test in
Song et al. (2008), and HVLT in Wang et al. (2015). Two-
thirds of significant outcome variables pertained to word list
recall tasks. Most immediate and delayed free recall scores
indicated significant impairment, but the three studies meas-
uring recognition did not show a significant difference
between patients and controls. Very large ES were also found
in naming tasks (g=−1.40).
DISCUSSION
Summary of Findings
MCI-LB
In this structured review, only one study on the cognitive
profile of MCI-LB utilised a control group. Kemp et al.
(2017) reported prodromal DLB to have a profile of diffuse
impairments in the domains of EF, processing speed, atten-
tion, WM, visuospatial ability and visuospatial construction,
verbal memory and language. Kemp et al. (2017) provided
evidence of immediate and delayed verbal recall deficits in
prodromal DLB compared to controls, although recognition
Fig. 2. Bias-corrected effect sizes of visuospatial copying and recall tasks in PD-MCI relative to controls in both individual studies
(circles) and as a summary effect size by group (diamonds). BVMT =Brief Visuospatial Memory Test; ROCF =Rey–Osterrieth
Complex Figure.
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memory was intact. This study indicates that a substantial
number of MCI-LB will present with verbal memory impair-
ment at this early stage and it should not therefore be taken as
a reliable indicator of prodromal AD (Kemp et al., 2017).
However, ES of verbal memory impairment reported in
MCI-LB (g=−058; Kemp et al., 2017) were almost half that
of the pooled estimate for PD-MCI (g=−1.25).
Given that the largest deficits overall in prodromal DLB
were in EF (g=−1.65) and processing speed (g=−1.16),
it is possible that domain-general impairments could at least
partly account for deficits across other cognitive functions
(Kemp et al., 2017). Slowed speed of processing, executive
dysfunction, or praxic and perceptual impairments in prodro-
mal DLB could confound interpretation of deficits in more
complex tasks such as visual construction or naming tests,
as well as the greater impairments on visual versus verbal
memory scores reported by Kemp et al. (2017). Executive
dysfunction, for example, has the potential to impair cogni-
tion at various stages, including encoding and retrieval in
the case of memory function, thereby compounding the
impact (Bryan et al., 1999) Kemp et al.’s(2017) emphasis
on the role of EF in prodromal DLB is in line with a recent
report that another measure of EF (verbal fluency) had the
highest predictive accuracy for conversion to DLB in
idiopathic RBD patients (Génier Marchand et al., 2018).
EF similarly emerges as a potential explanatory factor in
PD-MCI results, as discussed further below.
Only six other studies (Bussè et al., 2018;Cagninetal.,
2015; Donaghy et al., 2018; Jicha et al., 2010; Sadiq et al.,
2017; Yoon et al., 2015) resulted from the systematic review
and used MCI-AD rather than a control group for comparison.
This illustrates both the dearth of neuropsychological research
in MCI-LB and the current focus on AD in the field. However,
the small number of results in this key population may also
relate to the challenge of identifying MCI-LB patients. Both
DLB and PDD are under-diagnosed, and regional (geographic)
differences in prevalence rates suggest varying clinical aware-
ness of Lewy body disease (Kane et al., 2018). The retained
studies provided limited evidence for MCI-LB and MCI-AD
differentiation, as only about a third of extracted measures
differed between groups and the findings within domains
are sometimes inconsistent, with MCI-LB statistically differ-
ing from MCI-AD on some but not all tasks in the same
domain. Verbal learning and memory appeared preserved in
MCI-LB relative to MCI-AD, in line with the pronounced
memory encoding deficits of AD (Lange et al., 2002;
Martin, Brouwers, Cox, & Fedio, 1985). However, without
the use of HCs, it cannot be inferred that verbal impairment
relative to controls should not be expected in MCI-LB cohorts.
PD-MCI
Our quantitative analyses emphasise that there are significant
deficits in PD-MCI relative to HCs. Overall, the highest
proportion and most severe of deficits was observed in the
visuospatial domain, although the verbal and EF domains
were also consistently impaired. One of the largest
differences between PD-MCI and controls was in Benton’s
JOLO task (Benton et al., 1983). JOLO, unlike many other
visuospatial tasks, requires minimal motor skill and is free
of practice effects (Montse, Pere, Carme, Francesc, &
Eduardo, 2001). As such it may be particularly useful in
tracking cognitive decline with PD progression. There was
less consistency in the attention and WM data, with half of
the papers showing deficits in some but not all reported tasks.
Similarly, the magnitude of deficit on semantic verbal fluency
tasks differed widely between studies, suggesting unreliabil-
ity when quantifying the extent of executive dysfunction in
patients. Our review found a slightly larger ES of impairment
in semantic than phonemic verbal fluency tasks in PD-MCI,
in line with findings from a meta-analysis in PD (Henry &
Crawford, 2004). Semantic fluency tasks make demands
on temporal functions and are typically challenging for AD
patients (Henry, Crawford, & Phillips, 2004), while pho-
nemic verbal fluency is more closely associated with frontal
abilities (Troyer, Moscovitch, Winocur, Alexander, & Stuss,
1998). This suggests firstly that caution should be taken when
utilising semantic and phonemic verbal fluency tasks inter-
changeably as indicative of executive dysfunction, for exam-
ple, in the case of current PD-MCI criteria (Litvan et al.,
2012). Secondly, this could suggest that co-occurring AD
pathology accounts for semantic fluency impairment in
PD-MCI. However, recent work by El-Nazer et al. (2019)
concluded that PD and PD/AD mixed pathologies do not
differ clinically and that cognitive deficits are associated with
both LB and AD pathological burden. Specifically, greater
Lewy body density was found in limbic and cortical struc-
tures in PD patients with poor verbal fluency, but higher
AD pathology was on trend in many of the same areas.
Recall Versus Recognition in PD-MCI
PD-MCI-associated deficits in figure copying (g=−1.56)
were more pronounced than in recall (immediate g=−0.91
and delayed SMD g=−1.03 recall), although all ES were
large. Conversely, visuospatial recognition is much less
impaired (Song et al., 2008), as also emerged in the MCI-
LB results. It is possible that complex figure recall is a more
challenging task for both patients and controls, and thus less
difference between groups is observed. The use of retention
scores (the percentage of information lost or gained between
copy and recall conditions) might provide more nuanced
information on differential abilities (Shin, Park, Park, Seol,
& Kwon, 2006). Recognition memory for word list stimuli
seems similarly intact in PD-MCI, in contrast to deficits in
both immediate and delayed recall conditions. This pattern
of dysfunction in both the visuospatial and verbal domains
in PD-MCI suggests impaired retrieval and relatively intact
encoding and storage mechanisms (Shin et al., 2006). This
supports the established retrieval deficit hypothesis of
memory impairment in PD (Tröster & Fields, 1995;
Whittington, Podd, & Kan, 2000), which argues that the cause
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of memory impairment is inability to retrieve material on
demand rather than encoding or retention ability (Mahurin,
Feher, Nance, Levy, & Pirozzolo, 1993). Given that a similar
pattern emerged in MCI-LB (Kemp et al., 2017), this model
may apply to other early alpha-synucleinopathies.
However, there has been increasing scrutiny of this hypoth-
esis and evidence of recognition impairment in some patients
(Higginson, Wheelock, Carroll, & Sigvardt, 2005; Whittington
et al., 2000). Whittington et al. (2000) found impairment in
recognition in PD participants without dementia, but not in
newly diagnosed PD patients, and Bronnick, Alves, Aarsland,
Tysnes and Larsen (2011) found that early PD patients
performed poorly on free recall, cued recall, and recognition
memory. Bronnick et al. (2011) attribute this impairment to
encoding failure due to poor EF, rather than to impaired
retrieval. Indeed, PD participants used fewer semantic cluster-
ing strategies to enhance their recall, and both strategy and EF
explained significant variance in learning. Earlier, Gershberg
and Shimamura (1995) and Hirst and Volpe (1988)had
demonstrated that frontal lobe lesion patients were unable to
capitalise on the potential semantic organisation present in
word lists. It is likely that the prominent EF impairments in
PD-MCI at least partly explain poorer performance on tasks
of greater complexity, regardless of domain.
Executive Function Weighting Impairs
Performance in PD-MCI
Impairment was found on only two-thirds of visuospatial
WM measures despite the high proportion of visuospatial
learning and memory tasks (91%) that show deficits in
PD-MCI. One question is why visuoconstructional ability
is impaired but not visuospatial WM? Figure copying such
as ROCF is a complex task that requires EFs such as
sustained attention, planning, and organisation (Shin
et al., 2006), in addition to the visuospatial perception
and processing that is required in visuospatial WM tasks like
Corsi blocks. If executive demands are responsible for this
divergence, this emphasises the methodological importance
of locating the executive processes within tasks with face
validity in other domains. However, even simple WM tasks
such as Digits Forward could be argued to have an EF
component (e.g. chunking), so this issue may speak more
to the debate regarding multicomponent versus unitary
models of WM (Cowan, 1999; Engle, Tuholski, Laughlin,
& Conway, 1999) than to a salient difference in a patient
population.
MCI Classification
Defining MCI neuropsychologically using domain cut-off
scores may also have the potential for circularity in analyses
in which neuropsychological performance is the phenotype
of interest. In the PD-MCI, all but one study (Anderson,
Simpson, Channon, Samuel, & Brown, 2013) defined groups
using neuropsychological criteria. PD-MCI studies tend to
utilise Movement Disorder Society (MDS) diagnostic criteria
for MCI, which is based on neuropsychological cut-off scores
by individual cognitive domain, typically between 1 and 2
SDs. However, the specific magnitude of deficit required
to be considered “impairment”has critical implications.
Dalrymple-Alford et al. (2011) found that while only 14%
of a PD sample was considered PD-MCI when defined as
two SDs below normative scores in at least two tests in a
domain, this number increases to 89% if considered at one
SD or more. In the latter scenario, 70% of clinically defined
HCs were also identified as MCI. To capture the breadth of
impairment, MDS criteria stipulate that cognition should
ideally be measured in five domains by at least two tasks,
but this increases the likelihood of reaching significance on
at least one measure. Few studies correct for multiple compar-
isons. Such a large amount of neuropsychological testing can
also become unwieldy to report in entirety and encourages
selection biases in presenting only significant results. Thus,
choosing a battery poses a problem: decreasing the breadth
may omit relevant individuals, but increased breadth often
leads to contradictory findings within domains. The use of
composite domain scores may help to overcome this meth-
odological challenge and has been suggested to bypass task
idiosyncrasy, avoid multiple comparisons, and increase
power (Crane et al., 2012; Gibbons et al., 2012).
While results suggest similarities in the neuropsychologi-
cal profiles of MCI-LB and PD-MCI by domain, future work
comparing these patient groups directly is warranted. For
example, poorer episodic memory ability might be expected
in MCI-LB given evidence of greater co-occurrence of amy-
loid and tau pathology in DLB versus PDD (Jellinger &
Korczyn, 2018). However, ES of verbal memory impairment
reported in MCI-LB (g=−0.58; Kemp et al., 2017) were
almost half that of the pooled estimate for PD-MCI
(g=−1.25) in the present study. A potential explanation
for this finding may be the greater variability expected in
DLB (Nelson et al., 2010) and MCI-LB. Indeed, the validity
of such direct comparisons of MCI subtypes may be chal-
lenged given the different definitional criteria for MCI cur-
rently in use.
The present review focused on studies with HC compari-
son groups that would provide closer matching between local
patients and controls. However, this approach does not
assume that important and complementary insights will not
be found in studies using normative data or other relevant
patient groups, such as stable or reverting MCI patients
(see supplementary table). Yarnall et al. (2014), for example,
found a high prevalence of MCI in their incidence cohort and
suggested that prominent executive dysfunction may account
for poor performance in other domains, such as memory
tasks, in line with the present review’s suggestions.
Longitudinal studies also critically offer insight into cogni-
tive trajectories in PD-MCI, and suggested that low baseline
EF, processing speed, visuospatial function, and verbal
memory were predictive of poorer outcomes at follow-up
(e.g. see Pigott et al., 2015; Williams-Gray, Foltynie,
Brayne, Robbins, & Barker, 2007).
Ciafone-Neuropsychology of MCI in Lewy body dementias 221
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In conclusion, growing interest in MCI due to Lewy body
disease necessitates a broader understanding of cognition in
early disease. The present study aimed to capture existing
literature in neuropsychological functioning by focusing on
studies in MCI-LB and PD-MCI. MCI-LB studies are limited,
but provide evidence for impaired EF, speed of processing,
visuospatial, WM, and attentional abilities in comparison
to controls and MCI-AD. However, results within domains
are at times inconsistent. PD-MCI shows deficits in visuospa-
tial, executive, and verbal tasks. However, these results
should be interpreted with caution due to issues of circularity.
MCI as a stable finding has also been called into question,
with 9% of individuals with established MCI later “reverting”
to normal cognition (Copeland & Schiess, 2013). Thus, while
PD-MCI may retain utility in clinical settings, it may be inap-
propriate as an a priori definition of a patient group in neuro-
psychological research. Defining MCI clinically [e.g. by
assessing independent function in daily activities, input from
family members, neurological examination, global cognitive
scales (MMSE) to rule out advanced or absent impairment, or
biomarkers], rather than neuropsychologically, will serve to
better capture the cognitive heterogeneity of early LBDs and
allow for more nuanced analyses of the potential interrelated-
ness of deficits.
ACKNOWLEDGEMENTS
This research was supported by the NIHR Newcastle
Biomedical Research Centre, Alzheimer’s Research UK
(A.T., grant number BH142057) and a Medical Research
Council studentship (J.C., MR/K501396/1).
CONFLICT OF INTEREST
A.T. has received support from GE Healthcare for investigator-
led research. No other authors have conflicts of interest to
disclose.
SUPPLEMENTARY MATERIAL
To view supplementary material for this article, please visit
https://doi.org/10.1017/S1355617719001103
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