Validation of Addenbrooke's cognitive examination for detecting ...

PSY-06255; No of Pages 4
Validation of Addenbrooke's cognitive examination for detecting early dementia in a
Japanese population
Hidenori Yoshida, Seishi Terada ⁎, Hajime Honda, Toshie Ata, Naoya Takeda, Yuki Kishimoto, Etsuko Oshima,
Takeshi Ishihara, Shigetoshi Kuroda
Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japan
article info
Article history:
Received 15 January 2008
Received in revised form 16 May 2009
Accepted 11 June 2009
Available online xxxx
Keywords:
Addenbrooke
ACE
Dementia
Cognitive evaluation
Japanese
1. Introduction
abstract
Early detection of dementia is an important challenge for the
physician, especially since the introduction of disease-modifying
treatments. Screening for early dementia requires a sensitive instrument
for assessment of cognition. The Mini-Mental State Examination
(MMSE) is a widely used cognition screening test in many parts of the
world (Folstein et al., 1975). However, it has limitations in screening
multiple cognitive domains and detecting early dementia (Teng et al.,
1987; Naugle and Kawczak, 1989; Feher et al., 1992). Addenbrooke's
cognitive examination (ACE) has been proposed as a simple and
effective instrument to detect dementia (Mathuranath et al., 2000).
Besides, it has been validated in the following languages: Malayalam
(Mathuranath et al., 2004), French (Bier et al., 2005), Spanish (García-
Caballero et al., 2006), German (Alexopoulos et al., 2006), and Danish
(Stokholm et al., 2009). Moreover, a revised version of ACE (ACE-R)
has recently been made available (Mioshi et al., 2006). Here, we report
our experience with this test and show that the Japanese ACE is
effective in detecting dementia in a Japanese-speaking population.
2. Methods
2.1. The instrument
The ACE was translated into Japanese with some adaptations concerning the nameand
address-learning and delayed recall tests, verbal fluency test, word and sentence
repetition tests, and reading tests (Table 1). In the tests of repetition, word reading and
⁎ Corresponding author. Tel.: +81 86 235 7242; fax: +81 86 235 7246.
E-mail address: terada@cc.okayama-u.ac.jp (S. Terada).
0165-1781/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.psychres.2009.06.012
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Psychiatry Research xxx (2009) xxx–xxx
Contents lists available at ScienceDirect
Psychiatry Research
journal homepage: www.elsevier.com/locate/psychres
There is a clear need for brief, but sensitive and specific, cognitive screening instruments for dementia. We
assessed the diagnostic accuracy of the Japanese version of Addenbrooke's Cognitive Examination (ACE) in
identifying early dementia in comparison with the conventional Mini-Mental State Examination (MMSE).
Standard tests for evaluating dementia screening tests were applied. A total of 201 subjects (Alzheimer's
disease (AD)=65, frontotemporal dementia (FTD)=24, vascular dementia=26, dementia with Lewy
bodies =11, mild cognitive impairment (MCI)=13, and controls=62) participated in this study. The
reliability of the ACE was very good (alpha coefficient=0.82). In our patient series, the sensitivity for
diagnosing dementia with an ACE score of ≤74 was 0.889 with a specificity of 0.987, and the sensitivity of an
ACE score of ≤80 was 0.984 with a specificity of 0.867. The Japanese version of the ACE is a very accurate
instrument for the detection of early dementia, and should be widely used in clinical practice.
© 2009 Elsevier Ireland Ltd. All rights reserved.
name and address recall, replacement with words of equivalent frequency and syllable
length in Japanese were made. On verbal fluency test, words beginning with the
letter ‘p’ were replaced by words beginning with the syllable ‘sa’ because the Japanese
language is based on syllables rather than letters. Thereafter, a bilingual expert not
familiar with the original ACE translated it back into English. The retranslated version
was very similar to the original one.
2.2. Subjects
We administered the ACE to 126 consecutive patients who had been referred to the
Memory Clinic of Okayama University Hospital and who had been diagnosed with
Alzheimer's disease (AD), vascular dementia (VaD), frontotemporal dementia (FTD), or
dementia with Lewy bodies (DLB) (Table 2). Sixty-two subjects who had no evidence of
organic dementing disorders or psychiatric diseases (30 men, 32 women; age range, 40–
80 years; mean age, 66.7±10.1 years) and 13 subjects with a Clinical Dementia Rating
(CDR) score of 0.5 without overt dementia who were recognized as having mild cognitive
impairment (MCI) (six men, seven women; age range, 43–83 years; mean age,
62.7 ±12.3 years) (Table 2) wereusedasacontrolgroups.
Sixty-five outpatients were diagnosed with AD (17 men, 48 women; age range,
46–87 years; mean age, 74.1 ± 7.8 years), 24 with FTD (13 men, 11 women; age
range, 48–77 years; mean age, 61.8 ± 9.1 years), 26 with VaD (18 men, eight
women; age range, 57–87 years; mean age, 73.4 ± 9.8 years), and 11 patients with
DLB (three men, eight women; age range, 67–87 years; mean age, 62.9 ± 8.1 years).
All patients with dementia had a dementia severity of 0.5 (suspicious) or 1 (mild)
based on the CDR (Hughes et al., 1982). All patients underwent general physical and
neurological examinations and extensive laboratory testing, including thyroid function tests,
serum vitamin B12, and syphilis serology, to exclude other potential causes of dementia. All
individuals and/or the nearest relative of the patient gave informed written consent.
The profile of each patient (age, sex, years of education, and years of disease
duration) was recorded, and the CDR score was rated by the chief clinician.
2.3. Diagnosis
All patients with AD met the criteria for probable AD formulated by the National
Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's
Please cite this article as: Yoshida, H., et al., Validation of Addenbrooke's cognitive examination for detecting early dementia in a Japanese
population, Psychiatry Res. (2009), doi:10.1016/j.psychres.2009.06.012

Table 1
Comparison between the original and the adapted versions of the ACE.
Item Original Adaptation
Orientation Year, season, date, day, month Unchanged. appropriate japanese year accepted as correct response
Country, county, town, hospital, floor Unchanged.
Attention/calc. 100-7 up to five subtractions Unchanged
saying “WORLD” backward Saying “fu-ji-no-ya-ma” backward
Memory Lemon, key, ball Unchanged
Seven-word address Seven-word address of local relevance
Remote memory UK PM (current and previous) Japan (current and previous)
UK (opposition leader), US (President) Japan (opposition leader), US (President)
Verbal fluency Letter “p” and animal Letter “Sa” and animal
Naming Pen, watch, giraffe, pig, crown, goat, camel, helicopter, kite,
windmill, kangaroo, barrel
Unchanged
Language comprehension Read and obey and 1-stage, 3-stage and complex grammar Unchanged
Repetition Brown, conversation, articulate Replaced with Japanese words of comparable frequency and length
Phrases Replaced with Japanese phrase of comparable complexity and length
Reading Regular words Replaced with “Kana” words of comparable frequency and word length
Irregular words Replaced with “Kanji” words of comparable frequency and word length
Visuospatial Overlapping pentagon, wire cube, clock-face drawing Unchanged
Disease and Related Disorders Association (NINCDS-ADRDA) group (McKhann et al.,
1984). All AD patients underwent head magnetic resonance imaging (MRI) and/or head
computed tomography (CT). AD patients with evidence of stroke, as determined either by
history or by imaging findings, were excluded. All patients with VaD met the criteria for
probable VaD formulated by the National Institute of Neurological Disorders and Stroke
and Association Internationale pour la Recherché et l'Enseignement en Neurosciences
(NINDS-AIREN) group (Roman et al., 1993). All VaD subjects underwent head MRI and/or
head CT, and had multiple lacunar infarcts of the basal gray matter and/or thalamus, in
addition to periventricular and deep white matter lesions. FTD was diagnosed according to
the international consensus criteria for frontotemporal lobar degeneration (FTLD) (Neary
et al., 1998). No patient suited the criteria for semantic dementia or progressive nonfluent
aphasia. All patients with DLB met the criteria for probable DLB formulated by McKeith et
al. (1996). All FTD and DLB patients underwent brain single-photon emission computed
tomography (SPECT) as well as head CT and/or head MRI.
2.4. Reliability
Inter-rater reliability was then evaluated by intraclass correlation coefficient (ICC)
on 20 consecutive patients admitted in our psychiatric department. Two investigators
evaluated patients at the same time but were blind to each other. Ten patients were
actively evaluated by one of them while the other passively observed, and their roles
were reversed for the other 10.
The internal consistency reliability within the ACE was assessed using Cronbach's
coefficient alpha (Cronbach and Meehl, 1955).
2.5. Statistical analysis
Statistical analysis was performed using the SPSS 14.0 J software program (SPSS
Inc., Chicago, IL, USA). A value of Pb0.05 was accepted as significant.
3. Results
Table 2 summarizes the socio-demographic characteristics and
scores on the ACE and MMSE for dementia and control groups in the
complete sample.
Inter-rater reliabilities of the ACE and MMSE were evaluated with
ICC of 0.994 and 0.986, respectively. The reliability of the ACE was
Table 2
Epidemiological data
n M/F Age Education CDR ACE MMSE
0 0.5 1
Normal 62 30/32 66.7±10.1 12.3±3.6 62 0 0 88.1±4.3 29.0 ±1.1
MCI 13 6/7 62.7 ±12.3 11.2±1.7 0 13 0 82.6 ±6.9 27.2±2.1
AD 65 17/48 74.1±7.8 10.1±2.4 0 25 40 63.3 ±7.8 21.7±2.9
FTD 24 13/11 61.8±9.1 12.4±2.5 0 4 20 61.8±16.0 22.5 ±4.9
DLB 11 3/8 75.5 ±5.0 9.8±2.4 0 3 8 62.9 ±8.1 22.8 ±2.8
VaD 26 18/8 73.4 ±9.8 9.9±3.0 0 13 13 64.8±7.9 22.6 ±2.8
M/F; male/female, age; years ±S.D., education; years±S.D., MMSE, ACE; mean score±
S.D.
MCI; mild cognitive impairment, AD; Alzheimer's disease, FTD; frontotemporal
dementia.
DLB; dementia with Lewy bodies, VaD; vascular dementia.
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measured in terms of internal consistency, using Cronbach's alpha
coefficient. The Cronbach's alpha for the ACE was 0.82.
Two methods were used to calculate the norms for the composite
score on the ACE. The first ACE cutoff score of 80/100 represented a
value two standard deviations (S.D.s) below the mean composite
score for the control group. The second cutoff was obtained by
estimating the probability of diagnosing dementia in the 202 subjects
in the clinic group. We estimated the sensitivity, specificity, and
positive predictive values (PPVs) for diagnosing dementia at different
prevalence rate (5, 19, 20, and 40%) for each ACE cutoff score from 70
to 80. A broad range of prevalence rates was chosen to encompass the
wide variation reported in various studies. A cutoff of 80 had high
sensitivity (98%) at a specificity of 87% (Table 3). A cutoff score of 74
had optimal sensitivity (89%) and specificity (99%), and maintained a
reasonably high PPV at different prevalence rates. Table 3 also shows
the sensitivity, specificity, and predictive values for diagnosing
dementia using the MMSE with a conventional cutoff of 24 and a
higher cutoff of 27 for the same sample population.
DSM-IV was used to estimate the criterion validity of the ACE
(composite score) in diagnosing dementia. The trade-off between
sensitivity and 1-specificity of the ACE and MMSE in diagnosing
dementia is shown in the receiver operating characteristics (ROC)
curve in Fig. 1. The area under the ROC curve (AUC) of the ACE was
0.987 and of the MMSE was 0.963.
Among the dementia group, the sensitivity and specificity for
diagnosing FTD with a Verbal-Language/Orientation Memory (VLOM)
ratio b2.2 was 16.7% and 96.1%, and the sensitivity and specificity for
diagnosing AD with a VLOM ratio N3.2 was 84.6% and 60.7%.
4. Discussion
4.1. Japanese version of ACE
This study was performed to evaluate the Japanese version of the
ACE in detecting early dementia. We compared the validity of the ACE
Table 3
Sensitivity and specificity of different ACE and MMSE cutoff scores for diagnosing
dementia, with corresponding probabilities of dementia (PPV) at different rates of
prevalence.
Test Cutoff Dementia PPV at different base rates
score Sensitivity Specificity 5% 10% 20% 40%
ACE 80/81 0.98 0.87 0.28 0.45 0.65 0.83
74/75 0.89 0.99 0.78 0.88 0.94 0.98
MMSE 27/28 0.95 0.83 0.22 0.38 0.58 0.79
24/25 0.76 0.97 0.60 0.76 0.88 0.95
Please cite this article as: Yoshida, H., et al., Validation of Addenbrooke's cognitive examination for detecting early dementia in a Japanese
population, Psychiatry Res. (2009), doi:10.1016/j.psychres.2009.06.012

Fig. 1. ACE and MMSE ROC curves for the detection of patients with dementia.
with the validity of the MMSE, which is a short test with widespread
international usage. We compared the diagnostic accuracy of the tests
not only with regard to sensitivity and specificity, but also with regard
to AUC. The AUC is independent of the decision criteria and less
contaminated by the external factors that affect the response
(Alexopoulos et al., 2006). Thus, the AUC provides a better measure
of predictive accuracy than the measurement's sensitivity and
specificity (Kim et al., 2005).
According to our findings, the Japanese ACE has excellent accuracy in
differentiating between patients with early dementia and cognitively
healthy participants. The ACE has good sensitivity and specificity in
detecting early dementia. The AUC value of the ACE for identifying early
dementia was 0.987. This value indicates excellent accuracy.
4.2. Difference between scores in the original ACE and Japanese ACE
(Table 4)
The two cutoff values for the original ACE were 88 and 83
(Mathuranath et al., 2000), while those for the Japanese ACE
composite were 80 and 74. Where does the difference come from?
Table 4 summarizes the mean individual component and composite
scores on the ACE for the cognitively normal groups of the original
study and this study. Exact statistical analysis cannot be conducted,
but the control group in this study had lower scores on memory and
verbal components than the control group in the original study. Tests
of both memory and verbal components include tests use language.
The Indo-European languages including English are written in letters,
whereas the Japanese language is written in syllables. A “seven-word
address” in the memory component of the Japanese version of the
ACE might be more difficult than that in the original ACE. In the
verbal fluency test also, the difference between letters and syllables
Table 4
Difference of scores between the original ACE and the Japanese ACE.
might affect the results. In English, the alphabet consists of 26
letters, whereas in Japanese, the “kana” writing system consists of 46
syllables. The number of words beginning with letter “p” might be
bigger than the number of words beginning with the syllable “sa”, and
therefore, saying words beginning with the syllable “sa” might be a
more difficult task than saying words beginning with the letter “p”.
4.3. VLOM ratio (Table 5)
We found that a VLOM ratio N3.2 indicated a better sensitivity in
detecting AD than reported by Mathuranath et al. (84.6% versus 75%),
but showed lower specificity (60.7% versus 84%) (Mathuranath et al.,
2000) (Table 5).
The major discordant finding in this study is the complete failure of
the ACE to detect FTD. In fact, only 16.7% of FTD cases had a VLOM ratio
b2.2. Our result is in line with that of Bier et al. (2004). The VLOM ratio
is the ratio between scores in language tasks and memory tasks. A
lower VLOM ratio indicates a specificdeficit in language rather than in
memory functions. In our dementia group, we had no case of primary
progressive aphasia or semantic dementia among our FTD patients,
who all presented with the pure frontal form of the disease. We agree
with the opinion of Bier et al. and think that a low (b2.2) VLOM ratio
may be effective in diagnosing the forms of FTLD with a selective
language deficit.
4.4. Limitations of this study
Our study has several limitations. The participants were recruited
at a university center. Thus, our results apply only to a clinic-based
patient population. The applicability and reliability of the ACE in
community samples require further investigation.
We used the clinical diagnosis based on a comprehensive diagnostic
workup and on international diagnostic criteria as the gold standard.
Despite the high validity of the diagnostic criteria, clinical diagnoses are
not always confirmed at autopsy. Thus, we should take into account the
possibility of erroneous clinical assessments. Therefore, the validity of
the ACE may be lower than our results suggest.
5. Conclusion
The Japanese version of the ACE is a very accurate instrument for the
detection of early dementia, and should be widely used in clinical practice.
n ACE MMSE Orientation Attention Memory Verbal Language Visuo⁎
Mathuranath, et al. 127 93.8 ±3.5 29.1±0.8 9.8±0.3 7.8±0.4 32.6 ±1.9 11.0±2.2 27.8±0.5 4.6±0.5
Yoshida, et al. 62 88.1±4.3 29.0 ±1.1 9.9±0.4 7.5±0.8 30.1±3.3 8.3 ±3.3 27.7±0.7 4.7±0.6
Scores; mean ±S.D., visuo⁎; visuospatial.
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H. Yoshida et al. / Psychiatry Research xxx (2009) xxx–xxx
Table 5
VLOM ratio.
n VLOM ratio
b2.2 2.2−3.2 3.2b
Normal 62 23 36 3
MCI 13 0 10 3
AD 65 1 9 55
FTD 24 4 10 10
DLB 11 2 8 1
VaD 26 1 12 13
MCI; mild cognitive impairment.
AD; Alzheimer's disease.
FTD; frontotemporal dementia.
DLB; dementia with Lewy bodies.
VaD; vascular dementia.
Please cite this article as: Yoshida, H., et al., Validation of Addenbrooke's cognitive examination for detecting early dementia in a Japanese
population, Psychiatry Res. (2009), doi:10.1016/j.psychres.2009.06.012
3

Acknowledgements
We thank Ms. Ido, Ms. Imai and Ms. Yabe for their skillful assistance
of this study. This work was supported by grants from the Japanese
Ministry of Education, Culture, Sports, Science and Technology, and
the Zikei Institute of Psychiatry.
References
Alexopoulos, P., Greim, B., Nadler, K., Martens, U., Krecklow, B., Domes, G., Herpertz, S.,
Kurz, A., 2006. Validation of the Addenbrooke's cognitive examination for detecting
early Alzheimer's disease and mild vascular dementia in a German population.
Dementia and Geriatric Cognitive Disorders 22, 385–391.
Bier, J.C., Ventura, M., Donckels, V., Van Eyll, E., Claes, T., Slama, H., Fery, P., Vokaer, M.,
Pandolfo, M., 2004. Is the Addenbrooke's cognitive examination effective to detect
frontotemporal dementia? Journal of Neurology 251, 428–431.
Bier, J.C., Donckels, V., Van Eyll, E., Claes, T., Slama, H., Fery, P., Vokaer, M., 2005. The
French Addenbrooke's cognitive examination is effective in detecting dementia in a
French-speaking population. Dementia and Geriatric Cognitive Disorders 19, 15–17.
Cronbach, L., Meehl, P., 1955. Construct validity in psychological tests. Psychological
Bulletin 52, 281–302.
Feher, E.P., Mahurin, R.K., Doody, R.S., Cooke, N., Sims, J., Pirozzolo, F.J., 1992. Establishing
the limits of the Mini-Mental State. Examination of ‘subtests’. Archieves of
Neurology 49, 87–92.
Folstein, M.F., Folstein, S.E., McHugh, P.R., 1975. Mini-Mental State: a practical method
for grading the cognitive state of patients for the clinician. Journal of Psychiatric
Research 12, 189–198.
García-Caballero, A., García-Lado, I., González-Hermida, J., Recimil, M., Area, R., Manes, F.,
Lamas, S., Berrios, G., 2006. Validation of the Spanish version of the Addenbrooke's
Cognitive Examination in a rural community in Spain. International Journal of
Geriatric Psychiatry 21, 239–245.
Hughes, C.P., Berg, L., Danziger, W.L., Coben, L.A., Martin, R.L., 1982. A new clinical scale
for the staging of dementia. British Journal of Psychiatry 140, 566–572.
Kim, K.W., Lee, D.Y., Jhoo, J.H., Youn, J.C., Suh, Y.J., Jun, Y.H., Seo, E.H., Woo, J.I., 2005.
Diagnostic accuracy of Mini-Mental Status Examination and Revised Hasegawa
Dementia Scale for Alzheimer's disease. Dementia and Geriatric Cognitive
Disorders 19, 324–330.
ARTICLE IN PRESS
4 H. Yoshida et al. / Psychiatry Research xxx (2009) xxx–xxx
Mathuranath, P.S., Nestor, P.J., Berrios, G.E., Rakowicz, W., Hodges, J.R., 2000. A brief
cognitive test battery to differentiate Alzheimer's disease and frontotemporal
dementia. Neurology 55, 1613–1620.
Mathuranath, P.S., Hodges, J.R., Mathew, R., Cherian, P.J., George, A., Bak, T.H., 2004.
Adaptation of the ACE for a Malayalam speaking population in southern India.
International Journal of Geriatric Psychiatry 19, 1188–1194.
McKeith, I.G., Galasko, D., Kosaka, K., Perry, E.K., Dickson, D.W., Hansen, L.A., Salmon, D.P.,
Lowe, J., Mirra, S.S., Byrne, E.J., Lennox, G., Quinn, N.P., Edwardson, J.A., Ince, P.G.,
Bergeron, C., Burns, A., Miller, B.L., Lovestone, S., Collerton, D., Jansen, E.N., Ballard, C.,
de Vos, R.A., Wilcock, G.K., Jellinger, K.A., Perry, R.H., 1996. Consensus guidelines for
the clinical and pathological diagnosis of dementia with Lewy bodies (DLB). Report
of the Consortium on DLB International Workshop. Neurology 47, 1113–1124.
McKhann, G., Drachman, D., Folstein, M., Katzman, R., Price, D., Stadlan, E.M., 1984.
Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group
under the auspices of Department of Health and Human Services Task Force on
Alzheimer's disease. Neurology 34, 939–944.
Mioshi, E., Dawson, K., Mitchell, J., Arnold, R., Hodges, J.R., 2006. The Addenbrooke_s
Cognitive Examination Revised (ACE-R): a brief cognitive test battery for dementia
screening. International Journal of Geriatric Psychiatry 21, 1078–1085.
Naugle, R.I., Kawczak, K., 1989. Limitations of the Mini-Mental State Examination.
Cleveland Clinical Journal of Medicine 56, 277–281.
Neary, D., Snowden, J.S., Gustafson, L., Passant, U., Stuss, D., Black, S., Freedman, M.,
Kertesz, A., Robert, P.H., Albert, M., Boone, K., Miller, B.L., Cummings, J., Benson, D.F.,
1998. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria.
Neurology 51, 1546–1554.
Roman, G.C., Tatemichi, T.K., Erkinjuntti, T., Cummings, J.L., Masdeu, J.C., Garcia, J.H.,
Amaducci, L., Orgogozo, J.M., Brun, A., Hofman, A., Moody, D.M., O'Brien, M.D.,
Yamaguchi, T., Grafman, J., Drayer, B.P., Bennett, D.A., Fisher, M., Ogata, J., Kokmen,
E., Bermejo, F., Wolf, P.A., Gorelick, P.B., Bick, K.L., Pajeau, A.K., Bell, M.A., DeCarli, C.,
Culebras, A., Korczyn, A.D., Bogousslavsky, J., Hartmann, A., Scheinberg, P., 1993.
Vascular dementia: diagnostic criteria for research studies. Report on the NINDS–
AIREN International Work Group. Neurology 43, 250–260.
Stokholm, J., Vogel, A., Johannsen, P., Waldemar, G., 2009. Validation of the Danish
Addenbrooke's Cognitive Examination as a screening test in a memory clinic.
Dement and Geriatric Cognitive Disorders 27, 361–365.
Teng, E.L., Chui, H.C., Teng, E.L., Chui, H.C., 1987. The Modified Mini-Mental State (3MS)
Examination. Journal of Clinical Psychiatry 48, 314–318.
Please cite this article as: Yoshida, H., et al., Validation of Addenbrooke's cognitive examination for detecting early dementia in a Japanese
population, Psychiatry Res. (2009), doi:10.1016/j.psychres.2009.06.012