J Neurol (2004) 251: 428–431 DOI 10.1007/s00415-004-0345-z
J. C. Bier M. Ventura V. Donckels E. Van Eyll T. Claes H. Slama P. Fery M. Vokaer M. Pandolfo
Received: 1 August 2003 Received in revised form: 10 November 2003 Accepted: 13 November 2003
J. C. Bier, MD · M. Ventura, MD · M. Vokaer, MD · M. Pandolfo, MD Dept. of Neurology Erasme Hospital Brussels, Belgium J.-C. Bier () Hôpital Erasme Service de Neurologie 3ème étage 808 route de Lennik 1070 Bruxelles, Belgium E-Mail:
[email protected] V. Donckels, MSc · E. Van Eyll, MSc · T. Claes, MSc · H. Slama, MSc · P. Fery, MSc, PhD Dept. of Neuropsychology Erasme Hospital Brussels, Belgium M. Ventura, MD Center for Traumatology & Rehabilitation Université Libre de Bruxelles Brussels, Belgium
ORIGINAL COMMUNICATION
Is the Addenbrooke’s Cognitive Examination effective to detect frontotemporal dementia?
■ Abstract We evaluated the Addenbrooke’s cognitive examination (ACE), a simple instrument to differentiate frontotemporal dementia (FTD) from Alzheimer’s disease (AD), in our dementia patients clinic population. The Verbal-Language/Orientation-Memory (VLOM) ratio, which compares its language and memory scores, determines whether FTD or AD is more likely. The ACE was translated into French with adaptation maintaining the number of words in the name and address learning and delayed recall test, and with cultural adaptation for the semantic memory. The 85 included subjects had no evidence of two or more organic pathologies, after at least six months of follow-up, and an MMSE score ≥ 20/30. Patients with cognitive impairment due to alcohol intake were excluded. The diagnosis of a specific dementing illness was based on the consensus of the neurologist and neuropsychologists in the team. Thereafter, another neurologist expert in de-
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Introduction Although dementing disorders are characterized by specific patterns of brain pathology and dysfunction [10], a clinically based differential diagnosis is often difficult. The Addenbrooke’s cognitive examination (ACE) [5] has been proposed as a simple and effective instrument to
mentia, blinded to the ACE result and to the diagnosis and treatment, reviewed all cases files and proposed a diagnosis. A diagnostic agreement was reached for 79 cases (92.9 %) with 40 (50.6 %) dementia: 25 AD (62.5 %), 9 FTD (22.5 %). We estimated that the sensitivity for detecting dementia of an ACE score ≤ 83/100 was 90 % with a specificity of 64.1 %. When the ACE score was ≤ 88/100, the sensitivity for diagnosing FTD of a VLOM ratio < 2.2 was 11.1 % with a specificity of 88 % and the sensitivity for diagnosing AD of a VLOM ratio > 3.2 was 72 %, with a specificity of 69.4 %. We conclude that, when used as originally proposed, ACE is very accurate for the detection of dementia, but much less effective in discriminating the most common frontal variant of FTD. ■ Key words Addenbrooke’s cognitive examination · frontotemporal dementia · Alzheimer’s disease · verballanguage/orientation-memory
differentiate frontotemporal dementia (FTD) from Alzheimer’s disease (AD) [3, 4]. The Verbal-Language/Orientation-Memory (VLOM) ratio, which compares language and memory scores in the ACE, determines whether FTD or AD is more likely. VLOM ratios < 2.2 for FTD and > 3.2 for AD are considered as highly sensitive (75 % for AD and 58 % for FTD) and specific (84 % for AD and 97 % for FTD) [5]. Here we report our
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experience with this test and show that the frontal form of FTD often escaped detection in our patient series.
Methods ■ The instrument The ACE was translated into French with adaptation of the name and address learning and delayed recall test, of the semantic memory test, of the repeating words and sentences tests, and of the reading regular and irregular words tests [5]. These modifications have maintained the number of words in the name and address learning and delayed recall test. The semantic memory test needed cultural adaptation. Particular attention was given to the length, frequency [1], and grammatical difficulties of the repeating tests and to the length and frequency of words for the reading tests. The VLOM ratio was calculated as proposed in the original paper [5]. Thereafter, a bilingual expert not familiar with the original ACE made a back-translation into English. The new version was very similar to the original one [5] except for the adapted points. The inter rater reliability was then evaluated on 10 consecutive patients admitted in our neurological department. Two investigators evaluated patients (J.-C. B., M.VKR.) in the same time but blind for each other. Five patients were actively evaluated by one of them while the other passively noted. Roles were exchanged for the other five. Patients had to take all parts of the test, even if these were considered unnecessary after a successful performance in a previous component of the test (e. g., spell “World” backwards). When patients failed a test item, they were encouraged to try again at least three times by the active investigator. Inter-rater reliabilities of ACE, VLOM and Mini Mental State Examination (MMSE) were evaluated with intraclass correlation coefficient (ICC) of respectively 0.9991 (CI95 %: 0.9988–0.9993; p < 0.001), 0.9990 (CI95 %: 0.9986–0.9993; p < 0.001) and 0.9982 (CI95 %: 0.9974–0.9988; p < 0.001). ■ Patients and procedure We evaluated the ACE in 285 patients who were followed up every 3 to 6 months by one of the authors (J.-C. B.) at the ERASME Hospital Memory Clinic between April 2001 and April 2003. The 85 included subjects had no evidence of two or more organic pathologies, at least after six months of follow-up, and an MMSE score ≥ 20/30. Patients with cognitive impairment due to alcohol intake were excluded. Forty-three patients had an MMSE < 20, 6 refused to perform the neuropsychological testing, 65 had a history of acute cognitive deterioration with one or more focal lesion seen on imaging or evidence of two or more organic pathologies, 4 had cognitive impairment due to alcohol intake and 82 had been followed for less than six months. Patients were subjected to a clinical, radiological (CT or MRI), and laboratory evaluation.All but four underwent standard neuropsychological test batteries, including an evaluation of orientation in time and space, a digit span, the Buschke selective reminding task, an informal investigation of verbal expression and comprehension, a linedrawings naming, a verbal fluency tasks, a clock drawing, the complex Rey figure, the Raven progressive matrix, the Trail Making test, the Stroop word-color interference test, the Tower of London and the Wisconsin Card Sorting test. The four patients who did not receive this evaluation had all been clinically followed for at least one year. The diagnosis of a specific dementing illness was based on the consensus of the neurologist and neuropsychologists in the team, who used evidence from all clinical and investigational results. Thereafter, another neurologist expert in dementia (M.Ve.), blinded to the ACE result and to the diagnosis and treatment, reviewed all cases files and proposed a diagnosis. Patients were classified in two groups, demented (n = 40) or non-demented (n = 39), according to Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) [1]. The diagnosis of AD (n = 25) was based on National Institute of Neu-
rological and Communicative Disorders and Stroke-AD and Related Disorders Association Criteria [6]. Patients who were diagnosed as FTD (n = 9) fulfilled the clinical criteria of the Work Group on Frontotemporal Dementia and Pick’s Disease [8] while the diagnosis of Dementia associated with Lewy Bodies (DLB) (n = 5) was based on the criteria published by McKeith et al. [7]. A PET and/or a SPECT scan of the brain were performed in all cases with a clinical diagnosis of FTD and DLB.
Results A diagnostic agreement was reached for 79 cases (92.9 %). Thirty-nine (49.3 %) subjects were found to be non-demented: 19 had a mood disorder with cognitive deterioration (48.7 %), 6 had mild cognitive impairment (15.4 %), 12 had no pathology (30.8 %), 1 had primary progressive aphasia (2.5 %) and 1 pure progressive amnesia (2.5 %). Forty patients (50.6 %) were diagnosed with a dementing illness: 25 with AD (62.5 %), 9 with FTD (frontal form) (22.5 %), 5 with DLB (12.5 %), and 1 with Hakim-Adams syndrome (HAS: 2.5 %). Disagreement occurred in six cases (7.1 %). They included 1 patient first diagnosed with the frontal form of FTD with parkinsonism who was re-evaluated by the blind investigator as a case Parkinson’s disease, a case first diagnosed as AD and another one evaluated as HAS who were considered by the blind investigator to have FTD, a case first evaluated as a mood disorder with cognitive deterioration, a second diagnosed as having a supranuclear palsy both re-evaluated as having AD by the blind investigator and a case first evaluated as MCI who was considered by the blind investigator to have a mood disorder with cognitive deterioration. Epidemiological data, MMSE and ACE scores, and VLOM ratios are shown in Table 1. We estimated that in our patient series the sensitivity for diagnosing dementia of an MMSE score ≤ 24/30 was 45 %, the sensitivity of an MMSE score ≤ 27/30 was 80 % with a specificity of 53.8 %, the sensitivity of an ACE score ≤ 83/100 was 90 % with a specificity of 64.1 %, the sensitivity of an ACE score ≤ 88/100 was 100 % with a specificity of 46.2 %. When the ACE score was ≤ 88/100, the sensitivity for diagnosing FTD of a VLOM ratio < 2.2 was 11.1 % with a specificity of 88 % and the sensitivity for diagnosing AD of a VLOM ratio > 3.2 was 72 %, with a specificity of 69.4 %.
Discussion Some results of the present study are concordant with the original observations by Mathuranath et al. [5] We confirm the good sensitivity of an ACE score ≤ 83/100 to detect dementia (90 %) which is even better than reported (79 %). This could be due to the exclusion of vascular dementia in our study. Indeed, the history of the cognitive deterioration and the presence of vascular lesions on cerebral imagery
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Table 1 Epidemiological data N
Gender Age W Year; SD
MMSE
ACE
VLOM-ratio
Mean; SD
>24 ≤24
>27 ≤27
Mean; SD
>83 ≤83
>88 ≤88
3.2
6 11 4
13 1 2 1 1
86,7; 6,1 91; 6,2 79,5; 8 82 88
12 10 2
9 9
10 3 6 1 1
6 2 1
12 10 1 1
20 6 5 1
73,8; 8,6 68,7; 13,6 62,6; 9,6 80
2 2
25 9 5 1
2 1
Non-demented Mood disorder Normal MCI PPAp PPAm
19 15 12 7 6 4 1 0 1 0
61,2; 10,1 66; 11 79; 5,4 63 51
28,3; 1,8 29,5; 1,1 26,5; 2,9 27 26
18 12 4 1 1
1
Demented AD FTD DLB HAS
25 15 9 4 5 3 1 1
71,8; 8,1 71; 9,2 71,8; 6,7 72
24,8; 2,5 25,4; 3,1 23; 1,2 27
15 6
10 3 5
2
5 3
1
7 2 4 1
1 23 7 5 1
1 4 1
5 6 3 1
18 2 2
N number of patient; W women; SD standard deviation; MMSE mini mental state examination; ACE Addenbrooke’s cognitive examination; MCI mild cognitive impairment; PPAp primary progressive aphasia; PPAm pure progressive amnesia; AD Alzheimer’s disease; FTD frontotemporal dementia; DLB dementia associated with Lewy bodies; HAS Hakim-Adams Syndrome
usually exclude the diagnosis of isolated degenerative disease while it is often difficult to distinguish pure vascular dementia from mixed dementia. Specificity was lower (64.1 %) than reported by Mathuranath et al (96 %) [5]. This is probably due to the inclusion of depressed patients in our series. In clinical practice, depression is often associated with, and may precede degenerative dementia [9]. Similarly, concerning the diagnosis of AD, we found that a VLOM ratio > 3.2 had analogous sensitivity to detect AD than reported by Mathuranath et al (72 % versus 75 %), but showed a lower specificity (69.4 % versus 84 %). The major discordant finding in our study is the complete failure of the ACE to detect FTD. In fact, only one of our nine FTD cases had a VLOM-ratio < 2.2; a significantly different result from that of Mathuranath et al (p = 0.017 by Fisher’s exact test). The VLOM ratio is a ratio between scores in language tasks and memory tasks; a lower score indicates a specific deficit in language versus 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 think that a low (< 2.2) VLOM ratio may be effective in diagnosing the forms of FTD with a selective language deficit, but is rarely obtained in the pure frontal form of the disease. We conclude that the ACE is a very accurate test for the detection of dementia and should be used in the every day clinical practice (cutoff of 88 has a sensitivity of 100 % in our series), but is much less effective in discriminating the most common frontal variant of FTD when used as originally proposed. Re-defining the VLOM ratio or its cutoff could be a way to increase its sensitivity. However, in case of cutoff redefinition, this would be at the expense of its specificity. Further prospective studies are needed to evaluate the efficiencies of such modifications. ■ Acknowledgement We thank Pr.J.P.Bier (†) for the back translation and Dr. E. J. Bartholomé for advice and careful reading of this paper.
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