International Psychogeriatrics: page 1 of 9 © International Psychogeriatric Association 2016

doi:10.1017/S1041610216001496

Addenbrooke’s cognitive examination III: diagnostic utility for

mild cognitive impairment and dementia and correlation with
standardized neuropsychological tests
...........................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

Jordi A. Matias-Guiu, Ana Cortés-Martínez, Maria Valles-Salgado, Teresa Rognoni,

Marta Fernández-Matarrubia, Teresa Moreno-Ramos and Jorge Matías-Guiu
Department of Neurology, Hospital Clínico San Carlos, San Carlos Institute for Health Research (IdISSC), Universidad Complutense de Madrid, Madrid,
Spain

ABSTRACT

Background: Addenbrooke’s Cognitive Examination III (ACE-III) is a screening test that was recently
validated for diagnosing dementia. Since it assesses attention, language, memory, fluency, and visuospatial
function separately, it may also be useful for general neuropsychological assessments. The aim of this study
was to analyze the tool’s ability to detect early stages of Alzheimer’s disease and to examine the correlation
between ACE-III scores and scores on standardized neuropsychological tests.
Methods: Our study included 200 participants categorized as follows: 25 healthy controls, 48 individuals with
subjective memory complaints, 47 patients with amnestic mild cognitive impairment and 47 mild Alzheimer’s
disease, and 33 patients with other neurodegenerative diseases.
Results: The ACE-III memory and language domains were highly correlated with the neuropsychological
tests specific to those domains (Pearson correlation coefficient of 0.806 for total delayed recall on the Free
and Cued Selective Reminding Test vs. 0.744 on the Boston Naming Test). ACE-III scores discriminated
between controls and patients with amnestic mild cognitive impairment (AUC: 0.906), and between controls
and patients with mild Alzheimer’s disease (AUC: 0.978).
Conclusion: Our results suggest that ACE-III is a useful neuropsychological test for assessing the cognitive
domains of attention, language, memory, and visuospatial function. It also enables detection of Alzheimer’s
disease in early stages.

Key words: Addenbrooke’s cognitive examination, cognitive screening, dementia, neuropsychological assessment, Alzheimer’s disease

Introduction studies has reported a good diagnostic ability to

discriminate between healthy people and patients
Addenbrooke’s Cognitive Examination (ACE) has with dementia.
been validated in several languages and possesses However, we need cognitive tools that are able
good diagnostic and psychometric properties for to detect neurodegenerative diseases, and especially
diagnosing Alzheimer’s disease (AD) and other AD, at earlier stages. Relatively few studies have
types of dementia (Mathuranath et al., 2000). The evaluated the utility of ACE for diagnosing mild
third version of this test, ACE-III, was recently cognitive impairment (MCI) (Crawford et al.,
developed and validated in English and in Spanish 2012; Larner and Mitchell, 2014; Menon et al.,
(Hsieh et al., 2013; Matías-Guiu et al., 2015; 2014). The ACE-III total score and scores of its five
Matías-Guiu et al., 2016a). Each of these validation cognitive domains (attention, memory, language,
verbal fluency, and visuospatial abilities) make it
potentially useful for detecting neurodegenerative
Correspondence should be addressed to: Jordi A. Matias-Guiu, Department of
Neurology, Hospital Clinico San Carlos, San Carlos Institute for Health
diseases in early stages and establishing a cognitive
Research (IdISSC), Universidad Complutense, Calle Profesor Martin Lagos profile that may aid in differential diagnosis
S/N, 28040, Madrid, Spain. Phone: +34676933312, +34913303511. Email: (Matías-Guiu et al., 2016b).
jordimatiasguiu@hotmail.com, jordi.matias-guiu@salud.madrid.org. Received
24 Apr 2016; revision requested 16 May 2016; revised version received 31 Jul
Our hypothesis was that ACE-III may be
2016; accepted 19 Aug 2016. useful to establish a cognitive profile and for the

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 2 J. A. Matias-Guiu et al.
assessment of early stages of AD. The purpose of
the present study is two-fold. First, we assessed
the correlation between ACE-III domains and the
neuropsychological tests specific to each cognitive
function in order to establish the ability of the
ACE-III to detect cognitive deficit affecting specific
domains. Second, we studied the diagnostic ability
of the ACE-III in patients with MCI and mild AD.
Methods
Study design
We conducted a prospective cross-sectional study
validating the ability of the ACE-III to detect
deficits in the cognitive domains of attention,
memory, language, and visuospatial abilities. This
research project was approved by the ethics
committee at our hospital.
Study sample
The study included 175 consecutively recruited
patients who visited our center between May 2014
and November 2015 due to cognitive symptoms.
Patients included in this study were different from
those that participated in the previous work of
validation of ACE-III in Spain (Matías-Guiu et al.,
2015).
The inclusion criteria were being aged 50
years or older and having sufficient physical
capability and auditory and visual acuity for the
neuropsychological assessment.
Patients were classified in four groups according
to the results from the diagnostic study:
1. Individuals with subjective memory complaints
but with no objective cognitive impairment. We
included patients reporting symptoms of memory loss
but whose neuropsychological tests did not indicate
cognitive impairment. Thus, age- and education-
adjusted scores were above the percentile 11–18
(scaled score 7 or higher). Other cognitive or
behavioral symptoms were not allowed in this group.
2 and 3. Patients with AD. We included all patients
meeting diagnostic criteria for amnestic mild cognitive
impairment (aMCI; global Clinical Dementia Rating:
0.5) (group 2) and mild AD (global Clinical Dementia
Rating: 1) (group 3) (Morris, 1993; McKhann et al.,
2011).
4. Patients with other causes of cognitive decline
(other types of dementia). This group included
patients with other neurodegenerative diseases (be-
havioral variant of frontotemporal dementia, primary
progressive aphasia, and atypical parkinsonism)
(Litvan et al., 1996; McKeith et al., 2005; Gorno-
Tempini et al., 2011; Rascovsky et al., 2011).
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Furthermore, a group of 25 healthy controls
(group 5) was recruited among healthy volunteers
and patients’ relatives. These were participants
presenting no neurological or systemic diseases
potentially affecting cognitive function, no current
psychiatric disorders, and no history of abusing al-
cohol or other substances. Healthy controls had no
cognitive and no functional impairment, according
to the Mini-Mental State Examination (MMSE)
adjusted for age and education > 24 (Blesa et al.,
2001), a global Clinical Dementia Rating equal
to 0, a Functional Activities Questionnaire (FAQ)
of 0 (Pfeffer et al. 1982; Morris, 1993), absence
of depression according to Hamilton Depression
scale (Hamilton, 1960), and absence of subjective
memory or cognitive complaints.
Neuropsychological assessment
All patients were evaluated by two neuro-
logists specialized in cognitive neurology and
by structural neuroimaging. Neuropsychologists
administered the MMSE and ACE-III (Spanish
version, available from www.neura.edu.au/frontier/
research/test-downloads).
Patients also completed a neuropsychological
assessment protocol including several tests from
NEURONORMA, a normative data project con-
ducted in Spain (Peña-Casanova et al., 2009).
This project is similar to Mayo’s Older Americans
Normative Studies (MOANS) in the USA. The
tests included in our study were as follows: memory
span (forward and backward digit spans), the Corsi
block-tapping test, Trail Making Test (TMT),
Symbol Digit Modalities Test (SDMT), Boston
Naming Test (BNT), Visual Object and Space
Perception Battery (VOSP; subtests for object
decision, progressive silhouettes, position discrim-
ination, and number location), Judgement of
Line Orientation (JLO), Tower of London-Drexel
University, Free and Cued Selective Reminding
Test (FCSRT), Rey–Osterrieth Complex Figure
Test (copy and memory), and Stroop Color–Word
Interference Test. Following the NEURONORMA
authors’ recommendations, a scaled score ≤ 5
(percentile ≤ 5) was considered deficient. We
also assessed participants’ functional status using
the Functional Activities Questionnaire (Pfeffer
et al., 1982) and the Clinical Dementia Rating
scale (Morris, 1993). The diagnostic groups were
created based on results from functional and
neurological assessments and scores on the battery
of tests listed above.
Statistical analysis
The statistical analysis was conducted using SPSS
Statistics 20.0 by IBM® and MedCalc® 16.4.3.
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Kolmogorov–Smirnov test was used to determine
normality. We calculated the Pearson correlation
coefficient between ACE-III total and cognitive
domain scores and specific neuropsychological
test results. All participants were included in the
correlation analyses. The α level of significance
was set at 0.05; p values < 0.05 were considered
statistically significant and led to rejection of the
null hypothesis. These values are indicated with an
asterisk (*). p values lower than 0.01 are marked
with two asterisks (**).
We also estimated receiver operating charac-
teristic curves (ROC) for discriminating between
groups. The gold standard was the neuro-
psychological study conducted by applying the
NEURONORMA test battery and comparing
results to the normative data obtained by that
project (Peña-Casanova et al., 2009). In the ROC
curve analysis, the control group and the group
with subjective memory complaints were combined
in order to estimate the area under the curve
(AUC) used to discriminate non-pathological from
pathological groups, and only participants aged 65
years or more were selected to avoid differences
in age between groups. The ROC curves were
compared using the method proposed by DeLong
et al. (1988).
Results
Mean age was 71.94 ± 8.67, 116 of the participants
were women (58%), and the mean duration of
formal schooling was 9.77 ± 5.02 years. Of all
participants included in the study, 25 were healthy
controls, 48 had subjective memory complaints, 47
had aMCI, 47 had AD, and 33 had other types
of dementia (12 with primary progressive aphasia,
11 with the behavioral variant of frontotemporal
dementia, and 10 with atypical Parkinsonism). The
demographic distribution and ACE-III scores of
each group are shown in Table 1. The mean scores
of the other cognitive tests are provided in Table 2.
Correlation between ACE-III cognitive
domains and neuropsychological tests
The ACE-III memory domain was very largely
correlated with the FCSRT (r = 0.806 for total
recall, p value < 0.0001 and r = 0.806 for
total delayed recall, p value < 0.0001) and also
correlated with recall at 30 minutes on the Rey–
Osterrieth Complex Figure Test (r = 0.554, p
value < 0.0001). The language domain was highly
correlated with the BNT score (r = 0.744, p
value < 0.0001). Visuospatial domain has a large
correlation with SDMT (r = 0.549, p value <
0.0001) and VOSP-number location (r = 0.501,
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ACE-III for mild cognitive impairment and dementia 3
p < 0.0001), and a medium correlation with the
copy task of the Rey–Osterrieth complex figure (r
= 0.461, p value < 0.0001), VOSP-object decision
(r = 0.348, p value < 0.0001), VOSP-position
discrimination (r = 0.407, p value < 0.0001),
and with JLO (r = 0.498, p value < 0.0001).
The correlation between ACE-III visuospatial and
VOSP-progressive silhouettes was small (r = –
0.233, p value = 0.0005).
The ACE-III attention domain showed a
medium correlation with the following tests:
verbal span backward, visuospatial span forward,
visuospatial span backward, TMT part A, TMT
part B, SDMT, ROCF copy accuracy, FCSRT,
ROCF memory, Stroop test, VOSP-number loca-
tion, and JLO. The correlation with the Tower of
London was small. None of the tests showed a large
correlation with the ACE-III attention domain.
Regarding the ACE-III fluency domain, it showed
a large correlation with SDMT (r = 0.522, p <
0.0001), BNT (r = 0.549, p < 0.0001), FCSRT
total free recall (r = 0.550, p < 0.0001), and Stroop
part B (r = 0.645, p < 0.0001) and part C (r
= 0.543, p < 0.0001), and it showed a medium
correlation with verbal span backward, TMT
part B, the other scores of the FCSRT, ROCF
memory, Stroop part A, and Tower of London total
moves score. Table S1 (available as supplementary
material attached to the electronic version of
this paper at www.journals.cambridge.org/jid_IPG)
shows the correlations of ACE-III and its domains
with other tests.
Furthermore, the correlation between ACE-
III (total score) and MMSE was 0.820 (p <
0.0001). The ACE-III (total score) showed a large
correlation mainly with BNT (r = 0.687, p <
0.0001) and with the FCSRT (especially with total
recall, r = 0.694, p value < 0.0001, and delayed
total recall, r = 0.691, p value < 0.0001). The
correlation was lower but still large or medium
with verbal span forward, verbal span backward,
Corsi’s test forward, Corsi’s test backward, TMT
part A, TMT part B, SDMT, ROCF memory at
3 and 30 minutes, Stroop test, JLO, and VOSP
(Table S1).
For the memory domain, the AUC discrim-
inating deficient scores (scaled score ≤ 5) from
normal scores (scaled score ≥ 6) on the FCSRT
(delayed total recall) was 0.902. The language
domain AUC for detecting deficient scores on the
BNT was 0.909. The AUC of the attention domain
for detecting a TMT-B/TMT-A ratio of at least
3 (suggestive of executive dysfunction) was 0.667,
and for detecting impairment in Tower of London
(correct moves), the AUC obtained was of 0.799.
The AUC of the visuospatial domain was 0.780
to detect impairment in JLO, 0.797 in ROCF
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 4 J. A. Matias-Guiu et al.

Table 1. Clinical and demographic characteristics of diagnostic groups

SUBJECTIVE
M E M O RY
CO N T RO L S CO M P L A I N T S aM C I , C D R A D, C D R 1 OT H E R T OTA L
(N = 25) (N = 48) 0.5 (N = 47) (N = 47) (N = 33) (N = 200)
............................................................................................................................................................................................................................................................................................................................

Women, n (%) 17 (8.5%) 22 (11%) 26 (13%) 37 (18.5%) 14 (7%) 116 (58%)

Age (years) 65.76 ± 10.16 67.44 ± 8.18 75.85 ± 6.32 75.00 ± 7.25 73.24 ± 7.82 71.94 ± 8.67
Education 12.40 ± 4.99 10.46 ± 5.77 9.68 ± 4.50 7.17 ± 3.23 10.61 ± 5.31 9.77 ± 5.02
(years)
Total MMSE 28.76 ± 1.67 27.67 ± 2.63 24.47 ± 3.22 20.17 ± 4.23 23.36 ± 4.57 24.58 ± 4.61
score
ACE-III (total) 89.44 ± 8.66 83.06 ± 11.80 66.26 ± 10.84 50.94 ± 11.43 60.18 ± 16.00 68.59 ± 18.23
ACE-III 16.48 ± 1.55 15.85 ± 2.50 13.78 ± 2.34 10.76 ± 3.14 12.72 ± 4.22 13.73 ± 3.53
attention
ACE-III 22.48 ± 3.40 19.62 ± 4.21 12.02 ± 3.37 8.63 ± 3.07 12.48 ± 6.03 14.43 ± 6.38
memory
ACE-III 24.24 ± 2.00 22.95 ± 3.35 20.25 ± 4.28 16.38 ± 5.26 18.09 ± 5.42 20.13 ± 5.15
language
ACE-III fluency 16.48 ± 1.55 15.85 ± 2.50 13.78 ± 2.34 10.76 ± 3.14 12.72 ± 4.22 13.73 ± 3.53
ACE-III 14.64 ± 1.22 13.81 ± 2.04 12.00 ± 2.24 10.00 ± 2.85 11.69 ± 3.30 12.24 ± 2.92
visuospatial

Table 2. Main neuropsychological scores

SUBJECTIVE
M E M O RY
CO N T RO L S CO M P L A I N T S aMCI, CDR A D, C D R 1 OT H E R
(N = 25) (N = 48) 0.5 (N = 47) (N = 47) (N = 33)
............................................................................................................................................................................................................................................................................................................................

Verbal span forward 11.37 ± 3.17 11.69 ± 2.26 10.83 ± 3.15 9.96 ± 3.17 9.91 ± 3.41
Verbal span backward 11.29 ± 2.69 11.35 ± 2.68 10.34 ± 2.90 9.26 ± 2.65 8.85 ± 3.31
Corsi forward 11.08 ± 2.56 10.27 ± 2.53 9.11 ± 2.48 8.11 ± 3.23 8.39 ± 3.09
Corsi backward 10.96 ± 3.0 10.23 ± 2.70 9.11 ± 2.64 7.77 ± 2.90 8.48 ± 3.68
TMT-A 9.92 ± 2.0 8.12 ± 2.40 7.46 ± 3.07 5.61 ± 2.38 5.20 ± 4.52
TMT-B 9.42 ± 1.50 8.17 ± 2.42 7.10 ± 2.74 3.25 ± 2.09 4.52 ± 2.43
SDMT 9.79 ± 1.81 8.79 ± 2.04 7.62 ± 3.46 4.48 ± 2.37 5.31 ± 2.72
BNT 10.42 ± 2.14 9.57 ± 2.58 7.06 ± 2.93 5.11 ± 2.68 5.74 ± 3.32
VOSP-object decision 10.83 ± 3.14 10.54 ± 2.44 9.43 ± 2.24 7.53 ± 3.07 9.41 ± 2.53
VOSP-progressive silhouettes 10.67 ± 2.54 10.22 ± 2.47 10.40 ± 2.59 7.96 ± 3.61 10.39 ± 3.46
VOSP-discrimination position 13.92 ± 5.03 12.93 ± 5.68 9.96 ± 5.52 8.40 ± 5.32 10.09 ± 5.53
VOSP-number Location 12.71 ± 4.00 13.07 ± 5.00 9.55 ± 3.77 8.14 ± 4.12 9.29 ± 5.13
JLO 9.86 ± 2.88 9.23 ± 3.23 8.15 ± 2.83 5.05 ± 3.39 7.00 ± 4.32
ToL (correct moves) 10.25 ± 3.71 11.24 ± 2.89 8.78 ± 3.56 5.42 ± 3.98 6.50 ± 3.91
FCSRT total recall 9.83 ± 2.74 8.97 ± 2.89 2.76 ± 1.43 2.70 ± 1.86 4.60 ± 3.57
FCSRT delayed total recall 11.92 ± 3.90 10.44 ± 2.92 3.21 ± 1.66 2.96 ± 1.21 5.52 ± 4.00
ROCF copy accuracy 10.58 ± 2.97 9.48 ± 2.87 7.28 ± 2.29 6.25 ± 2.91 6.45 ± 3.40
ROCF memory (30 minutes) 10.46 ± 2.28 9.81 ± 2.29 5.58 ± 2.69 3.61 ± 2.13 6.50 ± 2.78
Stroop A 10.79 ± 2.16 9.61 ± 2.07 8.80 ± 2.38 7.42 ± 2.50 6.48 ± 2.72
Stroop B 10.25 ± 2.04 9.11 ± 2.28 8.29 ± 2.94 6.45 ± 2.29 4.79 ± 2.62
Stroop C 9.42 ± 2.33 8.98 ± 2.68 8.67 ± 3.14 6.34 ± 2.83 5.79 ± 2.98

(copy), 0.729 in VOSP-discrimination of position, between patient groups. The control group
and 0.777 in VOSP-number location. included participants from groups 1 and 5 (healthy
participants and those with subjective memory
complaints, respectively); participants older than
ACE-III: discriminant ability between groups 65 years were selected to limit age differences
We estimated the ROC curves for the ACE-III between the control group and the patient groups.
and domain scores that were able to discriminate In the group of patients with objective cognitive

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Figure 1(a). (Colour online) (a) ROC curves for discriminating between controls and patients with aMCI (CDR 0.5) using ACE-III, ACE-III
cognitive domains, and the MMSE. (b) ROC curves for discriminating between controls and patients with mild AD (CDR 1) using ACE-III,
ACE-III cognitive domains, and the MMSE. (c) ROC curves for discriminating between patients with aMCI (CDR 0.5) and those with mild
AD (CDR 1) using ACE-III, ACE-III cognitive domains, and the MMSE.
impairment suggestive of AD (aMCI and mild
AD), the AUC was 0.891 for ACE-III (total
score) and 0.942 for the memory domain, while
the AUC for the MMSE was smaller at 0.853.
Using the DeLong method, pairwise comparison of
ROC curves was performed. There were significant
differences between the AUC of memory domain
and MMSE (p = 0.007) and ACE-III-total score (p
= 0.01), but not between ACE-III-total score and
MMSE (p = 0.14).
For discrimination between patients with aMCI
(CDR 0.5) and healthy participants with subjective
memory complaints, the AUC was 0.817 for ACE-
III (total score), 0.906 for the memory domain,
and 0.778 for the MMSE (Figure 1a). The optimal
cut-off point for ACE-III (total score) was 73/74,
with a sensitivity of 76.6% and a specificity of
75%. For the memory domain, the optimal cut-
off point was 15/16, with a sensitivity of 87.2%
and a specificity of 80%. There were significant
differences between the AUC of memory domain
and MMSE (p = 0.005) and ACE-total score (p
= 0.003), but not between ACE-III (total score)
and MMSE (p = 0.30). The AUC discriminating
controls from patients with mild AD (CDR 1)
was 0.966 for ACE-III (total score), 0.978 for
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ACE-III for mild cognitive impairment and dementia 5
the memory domain, and 0.928 for the MMSE
(Figure 1b). The optimal cut-off point for ACE-
III (total score) was 63/64 with a sensitivity and
a specificity of 93.6% and 94.9%, respectively.
For the memory domain, the optimal cut-off point
was 13/14, with a sensitivity of 95.7% and a
specificity of 89.7%. There were no significant
differences among the AUC of ACE-III (total
score), the memory domain, and MMSE, although
a trend toward statistical significance was observed
between the AUC of the MMSE and memory
domain (p = 0.06) and between MMSE and
ACE-III (total score) (p = 0.09). Regarding
discrimination between patients with aMCI (CDR
0.5) and those with mild AD (CDR 1), the AUC
was 0.852 for ACE-III (total score), 0.786 for
the memory domain, and 0.789 for the MMSE
(Figure 1c), with no differences between the AUC
(p > 0.05).
Last, we analyzed the tool’s ability to discrim-
inate between controls and patients with other
neurodegenerative diseases. The AUC was 0.850
for ACE-III (total score), 0.816 for the memory
domain, 0.870 for verbal fluency, and 0.805 for the
MMSE, although there were no differences in AUC
between the different scores.
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 6 J. A. Matias-Guiu et al.

Figure 1(b). Continue

Figure 1(c). Continue

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Discussion
The present study indicates that ACE-III is a
useful tool that can assist in the diagnosis of
aMCI and mild AD. The correlation coefficients
obtained between each ACE-III domain and
neuropsychological tests specific to those cognitive
domains suggest that ACE-III is a useful screening
instrument contributing in detection of alterations
in some cognitive functions.
The memory domain was highly correlated with
the FCSRT; this correlation confirms the finding
of Hsieh et al. (2013) who observed a large
correlation between the memory domain and the
Rey Auditory Verbal Learning Test (0.59). The
correlation with the FCSRT was also stronger
than that observed between the Montreal Cognitive
Assessment and several other memory tests (Lam
et al., 2013). The high correlation with the
FCSRT is very interesting since that test has
demonstrated its high sensitivity for diagnosing
prodromal AD and for stratifying the risk of
progression to dementia (Sarazin et al., 2007). We
also observed a marked correlation between the
language domain and the BNT (r = 0.744), which
suggests that ACE-III may be useful for cognitive
disorders presenting with language impairment,
whether isolated or not, such as primary progressive
aphasia and AD (Leyton et al., 2010; Matías-
Guiu et al., 2014). The attention domain displayed
moderate correlations with tests related to attention
and executive function: Memory span, the Corsi
block test, TMT, SDMT, and Stroop Color–Word
Interference Test. These results are similar to those
reported by Hsieh et al. (2013) who found a
correlation of 0.42 between the attention domain
score and the Digit Span Test. This correlation
is lower than correlations with other domains,
a fact that may be due to including orientation
within the attention domain as well as the multiple
dimensions of the attention and the executive
function. Similarly, the correlation between verbal
fluency scores and executive tests was moderate,
and visuospatial domain scores, VOSP, and JLO
were also moderately correlated. There are several
reasons that probably explain why this correlation
was not stronger. The visuospatial domain involves
not only visuospatial tasks, but also constructional
praxis, which is influenced by visuospatial abilities
as well as other factors, such as executive function.
In addition, education has a significant impact
on constructional praxis, which may limit the
correlation between tests.
One of the most relevant finding of our study
was that the ACE-III discriminates well between
groups, in fact this test and specifically the memory
domain showed greater discriminant ability than
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ACE-III for mild cognitive impairment and dementia 7
the MMSE. The diagnostic ability of ACE-III was
also high in early stages of AD, especially in the
group with aMCI. The memory domain exhibited
the highest scores on the test, showing an AUC of
0.906 for diagnosis of the group with aMCI. This
domain also demonstrated the greatest diagnostic
ability for the group scoring 1 on the CDR and
for patients with suspected AD (CDR 0.5 and 1).
Memory domain scores were therefore most sensit-
ive for diagnosis, as their sensitivity and specificity
values show. However, the total ACE-III score
showed the highest discriminant ability between
CDR scores of 0.5 and 1, which suggests that this
score is the most appropriate indicator for patient
follow-up. This may be explained by the typical
course of cognitive decline in AD: During the first
stage (CDR 0.5), it presents memory impairment
only, while in the second stage (CDR 1) other cog-
nitive functions are affected (language, executive
function, etc.). In addition, this finding supports
the idea that the usefulness of certain scores
or domains depends on their clinical application
(screening for dementia, screening in early stages,
differential diagnosis, etc.) (Matías-Guiu and
Fernández-Bobadilla, 2014; Hsieh et al., 2015).
The cut-off point of ACE-III for detecting mild
AD (CDR 1) was 63/64, which is similar to the
cut-off point established by a previous validation
study conducted in our setting (Matías-Guiu et al.,
2015); 73/74 is the cut-off point for aMCI. While
these cut-off points are lower than those reported
by other validation studies of English-language
versions of ACE-R and ACE-III, they resemble
those reported for populations culturally closer to
our own, such as the Italian population (Pigliautile
et al., 2011). Differences in cut-off points may also
be linked to age and education differences between
patients (Jubb and Evans, 2015). Considering the
effect of these factors on test scores, normative data
may be more useful than cut-off points.
In the group of patients with other neuro-
degenerative diseases, the verbal fluency domain
and total ACE-III score were shown to have
the highest discriminant ability from controls.
This may have been the case because this
group included patients with language impairment
(primary progressive aphasia) and/or executive
dysfunction (frontotemporal dementia, atypical
parkinsonism) but with relatively well-preserved
memory. In any case, this group is smaller and, to a
certain extent, more heterogeneous; further studies
are necessary to evaluate the usefulness of ACE-III
in these patients, as well as in differential diagnosis
of neurodegenerative diseases (Elamin et al., 2015).
Our study has some limitations. First, in some
analyses, we have combined the groups’ healthy
controls and subjective memory loss, as well as
9 0 3D C 4 75D D D:7 ,3 4 697 , 7 D7 C C7 3 3 34 7 3D
 8 J. A. Matias-Guiu et al.
aMCI and AD. Although it is a controversial issue,
subjective memory complaints might be a very early
symptom of a neurodegenerative disorders (Pedro
et al., 2016). Furthermore, not all patients with
aMCI go on to develop AD. Due to the selection
criteria and the comprehensive neuropsychological
protocol used in this study (including FCSRT,
which has been specifically recommended for the
early diagnosis of AD), we think that it is unlikely
that patients with subjective memory complaints
included were at risk of AD, while most patients
with aMCI were, in fact, at high risk of developing
AD. However, further studies evaluating the role
of ACE-III in the prediction of progression of
aMCI and preclinical stages of AD would be very
informative. Another limitation was the fact that
AD patients were slightly less educated and older
than the control group. To reduce the effect of
this limitation, we estimated partial correlations,
correcting for age and years of education as
confounding variables.
In conclusion, our results suggest that ACE-
III is a useful tool for early diagnosis of AD and
assessment of cognitive function, and they support
using ACE-III as both a screening tool and a means
of describing cognitive profiles.
Conflict of interest
None.
Description of authors’ role
Jordi A. Matías-Guiu: Study concept and design,
interpretation of data, statistical analysis, writing
the manuscript, final approval of the manu-
script. Ana Cortés-Martínez: Acquisition of data,
statistical analysis, writing of the manuscript,
final approval of the manuscript. María Valles-
Salgado: Acquisition of data, literature search,
critical revision of the manuscript for important
intellectual content, final approval of the ma-
nuscript. Teresa Rognoni: Acquisition of data,
literature search, final approval of the manuscript.
Marta Fernández-Matarrubia: Interpretation of
data, literature search, final approval of the
manuscript. Teresa Moreno-Ramos: Acquisition
of data, critical revision of the manuscript for
important intellectual content, final approval of
the manuscript. Jorge Matías-Guiu: Study concept
and design, literature search, acquisition of data,
interpretation of data, study supervision, final
approval of the manuscript.
3676 :DD 53 4 697 9 5 7 ,: 7C7 2 7 CD . 9/
:DD 53 4 697 95 7 D7 C :DD 6H 6 9 1
Funding
None.
Supplementary material
To view supplementary material for this
article, please visit http://dx.doi.org/10.1017/
S1041610216001496
References
Blesa, R. et al. (2001). Clinical validity of the “mini-mental
state” for Spanish speaking communities. Neuropsychologia,
39, 1150–1157.
Crawford, S., Whitnall, L., Robertson, J. and Evans, J. J.
(2012). A systematic review of the accuracy and clinical
utility of the Addenbrooke’s cognitive examination and the
Addenbrooke’s cognitive examination-revised in the
diagnosis of dementia. International Journal of Geriatric
Psychiatry, 27, 659–669.
DeLong, E. R., DeLong, D. M. and Clarke-Pearson,
D. L. (1988). Comparing the areas under two or more
correlated receiver operating characteristic curves: a
nonparametric approach. Biometrics, 44, 837–844.
Elamin, M., Holloway, G., Bak, T. H. and Pal, S. (2015).
The utility of the Addenbrooke’s cognitive examination
version three in early-onset dementia. Dementia and
Geriatric Cognitive Disorders, 41, 9–15.
Gorno-Tempini, M. L. et al. (2011). Classification of
primary progressive aphasia and its variants. Neurology, 76,
1006–1114.
Hamilton, M. (1960). A rating scale for depression. Journal of
Neurology, Neurosurgery, and Psychiatry, 23, 56–62.
Hsieh, S. et al. (2015). The mini-Addenbrooke’s cognitive
examination: a new assessment tool for dementia. Dementia
and Geriatric Cognitive Disorders, 39, 1–11.
Hsieh, S., Schubert, S., Hoon, C., Mioshi, E. and
Hodges, J. R. (2013). Validation of the Addenbrooke’s
cognitive examination III in frontotemporal dementia and
Alzheimer’s disease. Dementia and Geriatric Cognitive
Disorders, 36, 242–250.
Jubb, M. and Evans, J. J. (2015). An investigation of the
utility of the Addenbrooke’s cognitive examination III in
the early detection of dementia in memory clinic patients
aged over 75 years. Dementia and Geriatric Cognitive
Disorders, 40, 222–232.
Lam, B. et al. (2013). Criterion and convergent validity of
the montreal cognitive assessment with screening and
standardized neuropsychological testing. Journal of the
American Geriatrics Society, 61, 2181–2185.
Larner, A. and Mitchell, A. J. (2014). A meta-analysis of
the accuracy of the Addenbrooke’s cognitive examination
(ACE) and the Addenbrooke’s cognitive
examination-revised (ACE-R) in the detection of dementia.
International Psychogeriatrics, 26, 555–563.
Leyton, C. E., Hornberger, M., Mioshi, E. and Hodges,
J. R. (2010). Application of Addenbrooke’s cognitive
examination to diagnosis and monitoring of progressive
9 0 3D C 4 75D D D:7 ,3 4 697 , 7 D7 C C7 3 3 34 7 3D

primary aphasia. Dementia and Geriatric Cognitive Disorders,
29, 504–509.
Litvan, I. et al. (1996). Clinical research criteria for the
diagnosis of progressive supranuclear palsy
(Steele-Ricardson-Olszewski syndrome): report of the
NINS-SPSP international workshop. Neurology, 47, 1–9.
Mathuranath, P. S., Nestor, P. J., Berrios, G. E.,
Rakowicz, W. and Hodges, J. R. (2000). A brief
cognitive test battery to differentiate Alzheimer’s disease
and frontotemporal dementia. Neurology, 55,
1613–1620.
Matias-Guiu, J. A. et al. (2014). Evaluation of the new
consensus criteria for the diagnosis of primary progressive
aphasia using fluorodeoxyglucose positron emission
tomography. Dementia and Geriatric Cognitive Disorders, 38,
147–152.
Matías-Guiu, J. A. and Fernández-Bobadilla, R. (2014).
Validation of the Spanish-language version of
Mini-Addenbrooke’s cognitive examination as a dementia
screening tool. Neurología. doi:10.1016/j.nrl.2014.10.005.
Matías-Guiu, J. A., Fernández-Bobadilla, R. and
Cortés-Martínez, A. (2016a). Addenbrooke’s Cognitive
Examination III: a neuropsychological test useful to screen
and obtain a cognitive profile. Neurología. Epub ahead of
print. doi: 10.1016/j.nrl.2016.06.014.
Matías-Guiu, J. A. et al. (2016b). Normative data for the
Spanish version of the Addenbrooke’s cognitive
examination III. Dementia and Geriatric Cognitive Disorders,
41, 243–250.
Matías-Guiu, J. A. et al. (2015). Validation of the Spanish
version of Addenbrooke’s cognitive examination III for
diagnosing dementia. Neurología, 30, 545–551.
McKeith, I. G. et al. (2005). Diagnosis and management of
dementia with Lewy bodies: third report of the DLB
consortium. Neurology, 65, 1863–1872.
McKhann, G. et al. (2011). The diagnosis of dementia
due to Alzheimer’s disease: recommendations from
3676 :DD 53 4 697 9 5 7 ,: 7C7 2 7 CD . 9/ 9 0
:DD 53 4 697 95 7 D7 C :DD 6H 6 9 1
ACE-III for mild cognitive impairment and dementia 9
the National Institute on Aging-Alzheimer’s
association workgroups on diagnostic guidelines for
Alzheimer’s disease. Alzheimer’s & Dementia, 7, 263–
269.
Menon, R., Lekha, V., Justus, S., Sarma, P. and
Mathuranath, P. (2014). A pilot study on utility of
Malayalam version of Addenbrooke’s cognitive examination
in detection of amnestic mild cognitive impairment: a
critical insight into utility of learning and recall measures.
Annals of Indian Academy of Neurology, 17, 420–425.
Morris, J. C. (1993). The clinical dementia rating (CDR):
current version and scoring rules. Neurology, 43,
2412–2414.
Pedro, M. C., Mercedes, M. P., Ramón, L. H. and Borja,
M. R. (2016). Subjective memory complaints in elderly:
relationship with health status, multimorbidity,
medications, and use of services in a population-based
study. International Psychogeriatrics. Epub ahead of print.
doi: 10.1017/S104161021600106X.
Peña-Casanova, J. et al. (2009). Spanish multicenter
normative studies (NEURONORMA project): methods
and sample characteristics. Archives of Clinical
Neuropsychology, 24, 307–319.
Pfeffer, R. I., Kurosaki, T. T., Harrah, C. H. Jr.,
Chance, J. M. and Filos, S. (1982). Measurement of
functional activities in older adults in the community. The
Journal of Gerontology, 37, 323–329.
Pigliautile, M. et al. (2011). Validation study of the Italian
Addenbrooke’s cognitive examination revised in a
young-old and old-old population. Dementia and Geriatric
Cognitive Disorders, 32, 301–307.
Rascovsky, K. et al. (2011). Sensitivity of revised diagnostic
criteria for the behavioral variant of frontotemporal
dementia. Brain, 134, 2456–2477.
Sarazin, M. et al. (2007). Amnestic syndrome of the medial
temporal type identifies prodromal AD: a longitudinal
study. Neurology, 69, 1859–1867.
3D C 4 75D D D:7 ,3 4 697 , 7 D7 C C7 3 3 34 7 3D