A validation study of the Chinese-Cantonese Addenbrooke’s Cognitive Examination Revised (C-ACER)

Participants and procedure

This was a cross-sectional validation study conducted at the cognitive clinic of the Medicine and Geriatric Department and the memory clinic of the Department of Psychiatry in a general hospital (United Christian Hospital, Kwun Tong, Kowloon, Hong Kong). Both clinics provide a specialist service to those presenting primarily with memory problems. Potential subjects were recruited from the two clinics during the study period from August 2011 to March 2012, and that included patients who were 60 years or older, Cantonese speaking with reasonable vision and hearing ability, and the ability to communicate verbally. Patients who had a history, as documented in medical records, of major depression, schizophrenia, epilepsy, significant head injury, substance abuse and alcoholism were excluded. Healthy participants were recruited among the patients’ spouses or those who attended an elderly vaccination program in the hospital. They shared the same inclusion and exclusion criteria.

We examined a total of 147 participants, divided into three groups: dementia (n = 54), mild cognitive impairment (MCI, n = 50), and normal control (NC, n = 43). All patient participants were examined by either the research geriatrician (CC) or psychogeriatrician (JLL) with a standard assessment battery, which included an interview with patients and informants, general and neurological examinations, mental state examination, laboratory tests (complete blood count, liver and renal function tests, thyroid function tests, serum vitamin B12 and folate level, and syphilis serology) and brain imaging (MRI or CT). Diagnoses of dementia and MCI were made according to DSM-IV criteria for dementia15 and Peterson’s criteria for MCI3 respectively. Each patient was staged functionally by the Global Deterioration Scale (GDS).16 Control subjects were assessed with the CMMSE, GDS and brief mental state examination by one of the researchers (CYY, CC or JLL), and participants in GDS stage 2 or below were confirmed to be normal controls. An independent research psychiatrist (LLW), who was blind to patients’ clinical findings, would then administer C-ACER to all participants within one week after the standard clinical assessment and obtain their demographic data (age, year of education). Written informed consent was obtained from all participants and this study was approved by the Hong Kong Hospital Authority Ethical Committee.

Sample size calculation

Based on the estimated prevalence rates of dementia and MCI at 12.5% and 8.5% respectively17, it was determined that the overall sample size was 138 (NC:MCI:dementia = 1:1:1) with n = 46 in each group, by using a sample size calculator available at http://www.medcalc.org/download/medcalcsetup.exe. These sample sizes would give a power of 0.8 and a Type I error of 0.05.

Measurements C-ACER

The original English ACER was translated into Chinese-Cantonese version by an expert panel with cultural and linguistic adaptation specific to the Hong Kong population. Modifications were made in the following subtests: name and address recall and recognition, semantic memory, verbal fluency, and reading and perceptual ability (fragmented letters). Based on the original criteria, a common Chinese name and local address (district, place, street and number) were constructed in the anterograde memory part. In the semantic memory subtest, the four questions were replaced by “the current Chief Executive of Hong Kong SAR”, “the year of Hong Kong’ reversion to China”, “the current president of the People’s Republic of China”, and “the first president of the People’s Republic of China”. In the verbal fluency subtest, since there is no equivalent substitution for letter fluency in Cantonese, the subtest was replaced by a second category fluency of naming vegetables in one minute. In the first part of the repetition subtest, the words “(weekend)”, “(contrast medium)”, “(rock and roll band)” and “(hiding one’s head in the sand)” were selected according to the criteria used in the original English ACER: multisyllabic words that are perceived as relatively difficult and rare yet known to most speakers. The relative frequencies of the four Chinese multisyllabic terms were chosen with comparable level of relative frequencies as that of the original English words in American word frequencies. For the second part of the repetition subtest, we substituted with short sentences used in MMSE in Taiwan or the People’s Republic of China. In the comprehension subtest, the instruction “point to the one which is a marsupial” was replaced by “point to the one which is a reptile” (the correct answer is “crocodile”) as the Chinese translation of marsupial () and kangaroo () are quite similar. In the reading subtest, as the words used in this reading task have to be “exception words” or “irregular words”, ie, words which do not obey the normal sound-to-print rules of English, five Chinese “exceptional” characters, () were selected. In the original version of the perceptual ability subtest, four incomplete English alphabets were used to assess perceptive visual agnosia as in the Visual Object and Space Perception Battery (VOSP)18. Therefore, we picked up four Chinese characters (also Chinese radicals) instead of four alphabets, and converted them into incomplete words by degrading them by 70% as in the development of VOSP.18 Finally, in the recognition subtest, two sets of name and local addresses (district, place, street and number) spreading across the territory were composed as recognition stimuli.

Global deterioration scale (GDS)

The GDS was developed to provide caregivers with an overview of the stages of functional decline for those suffering from a primary degenerative dementia.16 The GDS is comprised of 7 stages defined by a set of clinical characteristics. The higher the stage, the more severe the cognitive decline: Stage 1 = no cognitive decline; Stage 2 = subjective cognitive impairment; 3 = mild cognitive impairment; Stage 4 = mild dementia; Stage 5 = moderate dementia; Stage 6 = moderately severe dementia; Stage 7 = severe dementia. Inter-rater reliability for the GDS was found to be high (0.87–0.97) and scores of GDS showed high correlation with MMSE scores. We adopted GDS in this study to stage the cognitive level from a functional perspective.

Statistical analysis

All statistical analyses were performed using the Statistical Package for Social Sciences (SPSS) version 19 (IBM Corporation, Armonk, NY, USA), and a P value of <0.05 was considered statistically significant. For comparisons of continuous variables (age, years of education, total and sub-scores of C-ACER and score of CMMSE) among groups, one-way ANOVA was used. Chi-square tests were performed for categorical data. If differences attained statistical significance, multivariate linear regression analysis was carried out to examine the influence of demographic variables on the participants’ performance in the total and subdomain C-ACER scores. Logistic regression analysis was performed to assess the extent to which C-ACER and CMMSE scores could predict the clinical diagnosis, with age and years of education covaried. A threshold analysis and receiver operating characteristic (ROC) analysis were adopted to measure the performance of C-ACER. The performance of C-ACER was compared with that of CMMSE by comparing their AUCs, using a calculator available at http://www.medcalc.org/download/medcalcsetup.exe. The optimal cutoff was identified by calculating the Youden’s Index.19 Spearman’s correlation was used to investigate the convergent validity between total C-ACER scores and GDS scores.

Clinical characteristics

Demographic data, CMMSE and C-ACER total and component scores of the participants within the three groups are shown in Table 1. There was no significant difference in the years of education among groups. Subjects in the normal control group (NC) were significantly younger than those in the patient groups (NC = 72.8 years, MCI = 76.9 years, dementia = 79.2 years, CI = 78.1 years; P < 0.01). Post-hoc analysis showed that there were significant differences between the three groups (NC, MCI and dementia) regarding their performance in (1) CMMSE, (2) C-ACER total, (3) orientation/attention subtest, (4) memory subtest, (5) verbal fluency subtest, and (6) language subtest (P < 0.01). Concerning the visuospatial ability subtest, subjects with dementia scored significantly lower than those in the NC and MCI groups (P < 0.01), however, such difference was not observed between NC group and MCI group (P > 0.05).

In multivariate linear regression analysis (Table 2), with C-ACER total scores as the dependent factor while the age and years of education and the clinical diagnosis (NC vs MCI vs dementia) as the independent variables, only the latter two (ie, years of education and clinical diagnosis) were found to be affecting the C-ACER total scores significantly (P < 0.01). Same significance was demonstrated in four out of five C-ACER subdomains including orientation/attention, memory, verbal fluency and language (P < 0.01). Regarding visuospatial ability, the clinical diagnosis was shown to be the single significant factor.

Psychometric properties of C-ACER

In the first and second threshold analyses, the normal control (NC) was compared with the MCI group and dementia group respectively. In the third threshold analysis, patients with MCI or dementia were categorized in the “cognitively-impaired” group (CI, n = 104) for comparison against NC.

Table 3 shows the sensitivity, specificity and the areas under the ROC curve (AUC) at the optimal cut-off scores of C-ACER and CMMSE. The optimal cut-off was determined as the score where Youden’s index was maximized. The AUCs did not have significant differences between C-ACER and CMMSE regarding all three threshold analyses (P > 0.05). No differences in AUC were identified between ACER after adjustment of education level.

With regard to C-ACER, AUCs were 0.84, 0.98 and 0.91 for “NC vs MCI”, “NC vs dementia” and “NC vs CI” respectively. The optimal cutoff scores to distinguish NC from MCI and NC from the cognitively-impaired group were the same at 79/80, giving a sensitivity of 0.74 (NC vs MCI) and 0.88 (NC vs CI), and the same specificity of 0.84. At the optimal cutoff score of 73/74, ACER had high sensitivity (0.93) and specificity (0.95) to differentiate NC from dementia.

Logistic regression analysis reveals that (1) none of the covariates (age, years of education, C-ACER total and CMMSE scores; P > 0.05) contributed significantly to the differentiation between NC and MCI; (2) C-ACER total scores (regression coefficient = −0.29, P = 0.03) and years of education (regression coefficient = 0.59, P = 0.02) were independent factors to discriminate between NC and dementia while; (3) C-ACER total score (regression coefficient = −0.10, P = 0.04) was the single significant factor to differentiate NC from CI, independent of other covariates.

Reliability and convergent validity of ACER

The test-retest and inter-rater reliability of ACER, using Cronbach’s alpha coefficient, were both 1.00. The total C-ACER scores were significantly correlated with the scores of global deterioration scale (GDS, Spearman’s rho = −0.73, P < 0.01) and CMMSE (Spearman’s rho = 0.94, P < 0.01).