8. Grigoletto F, Zappal G, Anderson DW, Lebowitz BD.

Norms
for the Mini-Mental State Examination in a healthy population. Neurology 1999;53:315320.
9. OConnor D, Pollitt PA, Brook CP, Reiss BB, Roth M. Practice
observed: do general practitioners miss dementia in elderly
patients? BMJ 1988;297:11071110.
10. Roth M, Tym E, Mountjoy CQ, et al. The CAMDEX. A standardised instrument for the diagnosis of mental disorder in

CME

the elderly with special reference to the early detection of

dementia. Br J Psychiatry 1986;149:698 709.
11. Brayne C, Gill C, Paykel ES. Cognitive decline in an elderly
populationa two wave study of change. Psychol Med 1995;
25:673 683.
12. Roth M, Huppert FA, Tym E, Mountjoy CQ. CAMDEX. The
Cambridge Examination for Mental Disorders of the Elderly.
Cambridge, UK: Cambridge University Press, 1988.

A brief cognitive test battery to

differentiate Alzheimers disease and
frontotemporal dementia

P.S. Mathuranath, MD; P.J. Nestor, FRCAP; G.E. Berrios, MD; W. Rakowicz, MBBS; and J.R. Hodges, MD

Article abstractObjectives: To validate a simple bedside test battery designed to detect mild dementia and differentiate
AD from frontotemporal dementia (FTD). Methods: Addenbrookes Cognitive Examination (ACE) is a 100-point test
battery that assesses six cognitive domains. Of 210 new patients attending a memory clinic, 139 fulfilled inclusion criteria
and comprised dementia (n 115) and nondementia (n 24) groups. The composite and the component scores on the ACE
for the two groups were compared with those of 127 age- and education-matched controls. Norms and the probability
of diagnosing dementia at different prevalence rates were calculated. To evaluate the ACEs ability to differentiate early
AD from FTD, scores of the cases diagnosed with dementia with a Clinical Dementia Rating 1 (AD 56, FTD 24,
others 20) were compared. Results: Two cut-off values for the ACE composite score (88 and 83) were of optimal utility
depending on the target population. The ACE had high reliability, construct validity, and sensitivity (93%, using 88 as
cut-off). Using the lower cut-off of 83, the ACE had a higher sensitivity (82%) and predictive value than the Mini-Mental
State Examination for a wide range of dementia prevalence. The ACE differentiated AD from FTD, and the VLOM ratio
(derived using component scores: [verbal fluency language]/[orientation memory]) of 2.2 for FTD and 3.2 for AD
was highly discriminating. Conclusion: The ACE is a brief and reliable bedside instrument for early detection of dementia,
and offers a simple objective index to differentiate AD and FTD in mildly demented patients.
NEUROLOGY 2000;55:16131620

The need for screening and diagnostic tests to provide an objective measure of cognitive function has
increased over the last two decades largely as a result of three developments: 1) the realization that a
substantial proportion of patients previously diagnosed with AD have other pathologies, notably dementia with Lewy bodies1 and frontotemporal
dementia (FTD)2; 2) the advent of disease-modifying
treatments for AD, making it vital to establish an

Additional material related to this article can be found on the Neurology

Web site. Go to www.neurology.org and scroll down the Table of Contents for the December 12 issue to find the title link for this article.

early and accurate diagnosis, preferably in the predementia stage of the disease3; and 3) the enormous
increase in memory clinics, reflecting a growing concern in the general community about failing memory
in late life.4
Several screening and diagnostic tests for dementia have been developed,5,6 but no single test is the
established standard.3 More comprehensive cognitive
batteries such as the cognitive section (CAMCOG) of
the Cambridge Examination for Mental Disorders of
the Elderly (CAMDEX)7 and the Dementia Rating
Scale (DRS)8 require specialized test equipment or
trained personnel to administer, and are beyond the
scope of routine bedside cognitive evaluation. The
Mini-Mental State Examination (MMSE)5 is one of

See also pages 1601, 1609, and 1621

From the University of Cambridge Neurology Unit (Drs. Mathuranath, Nestor, and Hodges, and W. Rakowicz) and Department of Psychiatry (Dr. Berrios),
University of Cambridge, Addenbrookes Hospital; and MRC Cognition and Brain Sciences Unit (Dr. Hodges), Cambridge, UK.
Received December 27, 1999. Accepted in final form September 21, 2000.
Address correspondence and reprint requests to Professor John R. Hodges, MRC Cognition and Brain Sciences Unit, 15 Chaucer Road, Cambridge CB2 2EF,
UK; e-mail: john.hodges@mrc-cbu.cam.ac.uk
Copyright 2000 by AAN Enterprises, Inc.

Downloaded from www.neurology.org by Kathy Pieper on October 26, 2011

1613

the widely used and validated9 bedside instruments

for mental status evaluation, but has certain limitations, such as insensitivity to the early stages of AD
when the deficits are confined to an amnestic syndrome10,11 and to isolated frontal or linguistic deficits
found in early FTD12,13 and inability to differentiate
the type of dementia. This insensitivity stems from a
lack of measures of executive ability14 and the use of
extremely simple tasks for memory and language
functions that fail to detect deficits until they are
advanced.10 Modifications to the MMSE are warranted and have been attempted.15 Bearing these
factors in mind, we developed a new, theoretically
motivated, brief test battery for the detection and
classification of dementia based upon our research
over the last decade.11-13,16 Addenbrookes Cognitive
Examination (ACE) surveys key aspects of cognition
without the use of specialized test equipment. It is a
bedside or clinic-based schedule that incorporates
the MMSE, expands memory, language, and visuospatial components, and adds tests of verbal fluency.
The ACE has been administered over the last 3
years to all patients referred to the Cambridge Memory Clinic with cognitive complaints. We describe the
psychometric properties and normative values for
the instrument, compare it with the MMSE, and explore its ability to differentiate AD and FTD in a
group of patients with early dementia. The latter is
of particular relevance as a substantial proportion of
younger patients with dementia have FTD and, to
date, simple cognitive batteries have failed to differentiate AD from FTD.12,13,17,18
Methods. The instrument. The ACE, which can be
viewed as an Appendix on the Neurology Web site (www.
neurology.org), consists of six components evaluating separate cognitive domains. A maximum score of 100 is
weighted as follows: orientation (10), attention (8), memory
(35), verbal fluency (14), language (28), and visuospatial
ability (5). The orientation and attention components are
as in the MMSE. The memory component evaluates episodic memory (recall of three items from the MMSE plus a
name and address learning and delayed recall test) and
semantic memory. The language component includes naming 12 line drawings, comprehension, repeating words and
sentences, reading regular and irregular words, and writing. Visuospatial testing consists of copying overlapping
pentagons (from the MMSE) plus a wire cube, and drawing
a clock face. Verbal fluency consists of letter fluency for
words beginning with the letter P and category fluency for
animals. Raw scores are used for all items except for verbal fluency: a scaled scoring system for the letter and category fluency was derived using a Gaussian distribution of
the raw scores from normal controls included in this study
(see the Appendix at www.neurology.org). Scores for each
of the six domains can be calculated separately and their
sum gives the composite score on the ACE. The MMSE
score can also be calculated. The ACE can be administered
in 15 to 20 minutes.
Participants and procedure. The study evaluated the
ACE in 266 subjects consisting of two groupsa clinic
group (n 139) and a control group (n 127).
1614 NEUROLOGY 55

The 139 subjects in the clinic group were selected by

reviewing the case files of the 210 newly evaluated patients attending the Cambridge Memory Clinic between
June 1996 and October 1998. In this multidisciplinary
clinic patients undergo clinical, radiologic (SPECT scan,
CT, or MRI), and laboratory evaluation. In addition to
standard neuropsychiatric and neuropsychological test
batteries (including the Neuropsychiatric Inventory,19
Weschlers Adult Intelligence ScaleRevised,20 Wechslers
Memory ScaleRevised,21 Graded Naming Test,22 copying
the Rey Complex Figure,23 and Verbal Fluency Test24) they
are also administered the ACE and the Clinical Dementia
Rating (CDR) scale.25 Patients with suspected organic dementia syndromes are followed up in the clinic every 6 to
12 months. The diagnosis is based on the consensus of the
senior neurologist, psychiatrist, and neuropsychologist in
the team using evidence from all clinical and investigational results, but not the ACE. Based on postmortem verification of previously studied samples, our diagnostic
accuracy has been highamong 70 cases undergoing autopsy between 1992 and 1999, all 30 diagnosed in life with
AD had Alzheimer pathology, sometimes with other secondary pathologies.26
Patients. Of the 210 patients attending the clinic, 139
fulfilled the following criteria: 1) follow-up of at least 12
months; 2) able to complete full assessment; and 3) CDR
and neuropsychological tests completed within 90 days of
the ACE. Patients were excluded if they had 1) evidence of
two or more pathologies (e.g., AD with multiple infarcts on
neuroimaging), either of which could independently be the
cause of dementia; 2) major depression by Diagnostic and
Statistical Manual of Mental Disorders, 4th edition (DSMIV)27 or other psychiatric illness; and 3) causes of cognitive
impairment other than degenerative or vascular pathology
(e.g., closed head injuries, alcoholism). Of note was the fact
that 51 patients (36%) required a follow-up of 6 to 12
months before a consensus diagnosis could be reached.
Patients in the clinic group were classified into dementia (n 115) or nondementia (n 24) groups according to
DSM-IV.27 For subclassification, the diagnosis of AD (n
69) was based on National Institute of Neurological and
Communicative Disorders and StrokeAD and Related
Disorders Association criteria28 and vascular dementia
(VaD; n 14) on National Institute of Neurological Disorders and StrokeAssociation Internationale pour la Recherche et lEnseignement en Neurosciences criteria.29 In
keeping with our previous studies,12,13,30 the term FTD was
used as a general label for all focal lobar degenerations,
which includes patients with core feature of personality
and behavioral changes (frontal variant FTD), nonfluent
spontaneous speech (progressive nonfluent aphasia), and
fluent empty spontaneous speech with semantic breakdown (semantic dementia). All patients diagnosed with
FTD (n 29) conformed to the consensus criteria.2 Patients who failed to fulfill the criteria for AD, VaD, or FTD
were grouped as others (n 27) and consisted of patients
with dementia with Lewy bodies, corticobasal degeneration, or other miscellaneous organic syndromes. The severity of dementia was assessed using the CDR grading.25 It is
worth emphasizing that not all patients who fulfilled the
criteria for FTD met the DSM-IV criteria for dementia, as
impairment in memory, which is a core feature of DSM-IV,
is often absent in early FTD.12,17

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Table 1 Comparison of control, dementia (D), and nondementia (ND) groups on demographics and Addenbrookes Cognitive
Examination (ACE) subcomponent, component, and composite mean (SD) scores
Clinic group
D, n 115

Characteristics

p Value for D vs:

ND, n 24

Control, n 127

ND

Control

Demographics
Male sex

61

19

63

Age, y*

66.6 (8.9)

63.8 (7.0)

64.4 (9.3)

Education, y*

11.1 (2.6)

12.7 (3.6)

11.3 (2.6)

Orientation score (10)

7.3 (2.6)

9.8 (0.3)

9.8 (0.3)

Attention score (8)

6.0 (2.2)

7.7 (0.5)

7.8 (0.4)

17.8 (9.1)

30.3 (3.4)

32.6 (1.9)

13.9 (6.1)

19.4 (1.9)

20.3 (1.0)

ACE (maximum possible score)

Total memory score (35)

Name and address learning (21)

1.6 (2.1)

5.5 (1.5)

6.2 (1.0)

Verbal fluency (14)

Name and address delayed recall (7)

6.3 (3.0)

8.6 (3.2)

11.0 (2.2)

Letter P (7)

3.6 (1.9)

4.2 (1.8)

5.4 (1.4)

0.12

Category (7)

2.7 (1.6)

4.4 (1.6)

5.5 (1.2)

24.1 (4.8)

26.8 (2.5)

27.8 (0.5)

3.1 (1.7)

4.8 (0.4)

4.6 (0.5)

Language (includes naming) (28)

Visuospatial (5)
Mini-Mental State Examination (30)

21.8 (6.1)

29.8 (5.8)

29.1 (0.8)

ACE (composite score) (100)

64.8 (18.9)

88.0 (8.2)

93.8 (3.5)

* KruskalWallis test, p 0.20.

p 0.001, p 0.01 (Mann-Whitney U test, two-tailed).

Controls. The control group consisted of 127 age- and

education-matched individuals who were either attendees
at an orthopaedic (n 36) or gynecologic (n 28) clinic,
spouses of the attendees at the above clinics (n 26), or
members of the Medical Research Council subject panel
(n 37). Subjects with a history of head injury, drug
abuse, alcoholism, and neurologic or cognitive complaints
were excluded.
Results. Table 1 summarizes the demographic characteristics and mean (SD) individual component and composite scores on the ACE for the dementia, nondementia, and
control groups. Age and education were not significantly
different between the groups. The dementia group had sig-

nificantly lower scores than the control group on all components and the nondementia group on all except letter
fluency.
Normative data and validity. Two methods were used
to calculate the norms for the composite score on the ACE.
The first cut-off score of 88 represented a value two standard deviations below the mean composite score for the
control group. The second cut-off was obtained by estimating the probability of diagnosing dementia (in terms of
positive [PPV] and negative [NPV] predictive values) in
the 139 subjects in the clinic group. We estimated the
sensitivity, specificity, and predictive values for diagnosing
dementia at different prevalence rates (5, 10, 20, and 40%)
for each ACE cut-off score from 80 to 90. A broad range of

Table 2 Sensitivity and specificity of different ACE (and MMSE) cut-off scores for diagnosing dementia, with corresponding
probabilities of dementia (PPV) at different rates of prevalence
Dementia
Test/cut-off score

Sensitivity

PPV at different base rates

Specificity

5%

10%

20%

40%

ACE
88

0.93

0.71

0.14 (0.99)

0.26

0.44

0.68 (0.94)

83

0.82

0.96

0.51 (0.99)

0.69

0.83

0.93 (0.89)

27

0.74

0.96

0.48 (0.99)

0.66

0.82

0.92 (0.85)

24

0.52

0.96

0.40 (0.97)

0.58

0.76

0.89 (0.75)

MMSE

Figures in parentheses are the corresponding negative predictive values.

ACE Addenbrookes Cognitive Examination; MMSE Mini-Mental State Examination.
December (1 of 2) 2000

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NEUROLOGY 55

1615

Figure 1. Receiver operating characteristics of the Addenbrookes Cognitive Examination as a test for dementia.
prevalence rates was chosen to encompass the wide variation reported in various clinic31,32 and community-based33,34
studies. A cut-off of 88 had high sensitivity (93%) at a
specificity of 71% (table 2). A cut-off score of 83 had an
optimal sensitivity (82%) and specificity (96%), and maintained a reasonably high PPV and NPV at different prevalence rates of dementia. Table 2 also shows the sensitivity,
specificity, and predictive values for diagnosing dementia
using the MMSE with the conventional cut-off of 24 and a
higher cut-off of 27 for the same sample population. The
performance of the MMSE, although comparable to the
ACE in terms of specificity, was poor in terms of sensitivity
and predictive values.
Criterion validity. The DSM-IV was used as the gold
standard to estimate criterion validity of the ACE (composite score) in diagnosing dementia. The trade-off between
sensitivity (true positive rate) and 1 specificity (false
positive rate) of the ACE in diagnosing dementia is shown
in the receiver operating characteristics (ROC) curve35 in
figure 1. The area under the ROC curve is 0.91 (95% CI
0.85 to 0.99), which suggests that the ACE has a high

specificity for a large range of sensitivities. A false positive

diagnosis of dementia was made in 7 (5%) patients on
using the higher cut-off on the ACE, and in only 1 (0.7%)
when the lower ACE cut-off (83) or either of the MMSE
cut-off scores were used.
Construct validity. Construct validity evaluates how
well the results of a new test correlate with those of a
standard test for the same domain of interest. Construct
validity for the ACE for diagnosing dementia (as measured
against the DSM-IV) was good ( 0.62) using a cut-off
score of 88 and moderate ( 0.59) using a cut-off score of
83. The construct validity for the components of the ACE
was evaluated using data from neuropsychological tests
administered to a subgroup of controls, and was good for
the name and address delayed recall ( 0.69; against
story recall from Wechslers Memory ScaleRevised21) and
verbal fluency ( 0.60; against verbal fluency test with
letters F, A, and S24) and moderate for naming line drawings ( 0.41; against Graded Naming Test22) and visuospatial component ( 0.53; against copying the Rey
Complex Figure23).
Reliability. Reliability of the ACE was measured in
terms of internal consistency, using Cronbachs alpha coefficient. The Cronbachs alpha for the ACE was 0.78 (0.8
is considered excellent and 0.7 good).36
MMSE versus ACE. Table 3 shows the details of the
type and severity of dementia in cases correctly diagnosed
by the MMSE and the ACE. When compared with the
lower cut-off score of 83 on the ACE, the MMSE with a
conventional cut-off score of 24 missed dementia in 50% of
FTD cases, 26% of AD cases, and 30% of all dementia
cases. Even at a higher cut-off score of 27, the MMSE still
missed the dementia in 23% of FTD cases. The ACE with
higher cut-off of 88 had the highest sensitivity for detecting dementia in the clinic group, including in those with
AD (96%) and FTD (91%).
Severity of dementia and the ACE. A correct diagnosis
of dementia using the ACE (cut-off score 88) was achieved
in 82% of patients with CDR 1.0, 98% with CDR 1.0,
and 100% with CDR 1 (see table 3). Even with the lower
cut-off score of 83, the ACE diagnosed 79 of the 100 mild or
lesser grades of dementia cases (CDR 1), which was
considerably better than either of the MMSE cut-offs. Almost all dementia patients missed by the MMSE (cut-off

Table 3 Numbers (%) of patients correctly diagnosed with dementia on the ACE and the MMSE distributed by their type and severity
Dementia by ACE

Dementia by MMSE

Dementia type (n)

Cut-off 88

Cut-off 83

Cut-off 27

Cut-off 24

Total (115)

107 (93)

94 (82)

86 (75)

60 (52)

AD (69)

66 (96)

60 (87)

60 (87)

42 (61)

Frontotemporal dementia (22)

20 (91)

17 (77)

12 (54)

6 (27)

Vascular dementia (14)

12 (86)

8 (57)

7 (50)

6 (43)

9 (90)

9 (90)

7 (70)

6 (60)

CDR 1 (39)

32 (82)

26 (67)

20 (51)

9 (23)

CDR 1 (61)

60 (98)

53 (87)

51 (84)

37 (61)

CDR 1 (15)

15 (100)

15 (100)

15 (100)

14 (93)

Others (10)
Severity

ACE Addenbrookes Cognitive Examination; MMSE Mini-Mental State Examination; CDR Clinical Dementia Rating.
1616 NEUROLOGY 55

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Table 4 Comparison of mean scores on components of the

Addenbrookes Cognitive Examination: AD with non-AD and
frontotemporal dementia (FTD) with non-FTD
Components

AD, n 56

FTD, n 24

p Value*

Orientation

7.1 (2.2)

9.0 (1.3)

0.000

Attention

5.8 (2.0)

7.1 (1.3)

0.005

Memory Total

16.5 (7.4)

22.3 (7.2)

0.002

Name and address

learning

13.6 (5.7)

16.0 (4.2)

0.065

Name and address

delayed recall

1.0 (1.7)

3.2 (2.4)

0.000

6.7 (2.8)

5.5 (3.0)

0.101

Letter

4.0 (1.8)

2.9 (1.8)

0.012

Category

2.6 (1.5)

2.6 (1.6)

0.987

Language

25.0 (4.0)

21.8 (5.5)

0.003

Naming

10.7 (2.2)

8.5 (4.0)

0.014

3.1 (1.7)

3.9 (1.3)

0.066

Verbal Fluency

Visuospatial

Figure 3. Bar plot of the VLOM ratio ([verbal fluency

language]/[orientation memory]) against clinical diagnosis (pink frontotemporal dementia, yellow AD,
green others) in the study sample.

Values are mean (SD). Bold type indicates significance.

* MannWhitney U-test two-tailed significance.
Higher mean score where p 0.05.

Figure 2. Box plots comparing AD with frontotemporal

dementia (FTD) on subcomponents of the Addenbrookes
Cognitive Examination (ACE): (A) verbal (letter) fluency
and language; (B) orientation and delayed recall memory.

24) but detected by the ACE (cut-off 83) had a CDR 1.

The ACE thus maintained a good sensitivity for diagnosing
dementia in subgroups with differing dementia type and
severity.
Differentiating AD and FTD. Of the 139 patients in
the clinic group, the ACE (cut-off score 88) identified 114
as having dementia, of whom 100 (56 AD, 24 FTD, 10 VaD,
and 10 others) had a CDR 1. Comparison of the AD and
FTD subgroups on different components of the ACE revealed significant differences on orientation, attention, and
memory, which were worse in AD, and letter fluency, language, and naming, which were worse in FTD (table 4).
Figure 2 contrasts the performance of patients with AD
and FTD on the most discriminating subtests. In order to
translate this pattern of scoring into an index useful in
differentiating AD and FTD subgroups, we calculated the
ratio of scores on verbal fluency plus language to orientation plus name and address delayed recall memory. This
value, (VL)/(OM)the VLOM ratiotended to be
higher in patients with AD and lower in those with FTD.
For data on the sensitivity, specificity, and predictive values (at prevalence rates of 10, 20, 30, and 40%) of various
VLOM ratios for differentiating AD from non-AD (and
FTD from non-FTD), please access www.neurology.org. It
is clear that a VLOM ratio of 3.2 optimally differentiates
AD from non-AD (sensitivity 75% and specificity 84%), and
a ratio of 2.2 optimally differentiates FTD from non-FTD
(sensitivity 58% and specificity 97%). Figure 3 shows that
in the patient subgroup with an ACE score 88 and CDR
1 the majority with a VLOM ratio below 2.2 had FTD,
whereas above a ratio of 3.2 most had AD. Between 2.2
and 3.2, patients could have FTD, AD, or one of the other
dementias.
The demographic variables of age, years of education,
and gender were added to a logistic regression model as
covariates to determine their effect on the predictive outcome (dementia or nondementia) obtained using each of
the instrumentsACE (cut-off scores 88 and 83) and
MMSE (cut-off scores 24 and 27). Whereas none of these
demographic variables was significant at the 0.05 level for
either of the ACE cut-off scores, age (p 0.05) and gender
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NEUROLOGY 55

1617

(p 0.02) were found to be significant for both the MMSE

cut-off scores.

Discussion. Extensive experience with the ACE

suggests that it is a reliable instrument for the early
detection of dementia and meets most of the standards required by such an instrument.3
How the ACE differs from the MMSE. Since the
introduction of the MMSE over two decades ago5
there has been an enormous increase in our knowledge of the dementias and of normal cognition. The
major differences between the ACE and the MMSE
lie in the evaluation of memory, fluency, and language. The memory component of the ACE was expanded to reflect the importance of episodic memory
impairment in the early detection of AD.11,37,38 The
name and address delayed recall test appears to be a
particularly sensitive measure in AD. The ACE also
incorporates verbal fluency, which relies upon frontal executive function.39 Additionally, letter-based
fluency depends upon phonologic processing and
category-based fluency on semantic memory.40
Whereas letter-based fluency is particularly sensitive to FTD, category fluency is a marker of semantic
memory breakdown, including that in AD.41,42
The naming task in the ACE was made more difficult by having 12 line drawings of medium or low
frequency concept, based on the finding that naming
is highly dependent upon the concept frequency and
age of acquisition.43 In this study, the AD patients
performed well on naming tasks, reflecting their
mild disease. The changes to the nonsemantic aspects of language evaluation in the ACE are intended for early detection of FTD, particularly the
progressive aphasic variants.2,13 Changes to the
visuospatial section include adding a threedimensional wire cube copying and a clock face
drawing test, which have greater scope for detecting
impaired constructional abilities than copying a twodimensional figure.44,45 Both the AD and FTD groups
performed well on this component, reflecting the
very mild nature of the dementia in this cohort.
Psychometric properties of the ACE. The reliability of the ACE is evident in its high internal consistency, which indicates that all its component scores
contribute to the measurement of cognitive functions
and correlate well with the composite score, which in
turn determines the presence or absence of dementia. Among its various components, construct validity was best for memory and verbal fluency showing
good concordance with standard neuropsychological
tests. The ACE also showed good construct validity
for the diagnosis of dementia and had a high sensitivity, even with the lower cut-off score of 83.
Early diagnosis with the ACE. In the evaluation
of any new instrument, an important question to be
answered is how advanced dementia needs to be before the instrument can detect it. To address this
issue we used the CDR to grade the severity of dementia in functional terms.46 The majority of patients in this study had only mild or lesser grades of
1618 NEUROLOGY 55

dementia (CDR 1) when they received the ACE.

When the lower cut-off score of 83 was used, the ACE
detected dementia in 79% of all patients with dementia, a third more than that achieved using the conventional cut-off score of 24 on the MMSE. It
appeared particularly sensitive in FTD where it
nearly doubled the detection rate when compared to
the MMSE. In a third of all patients with dementia
in this study a clinical consensus diagnosis based
upon data from extensive assessments could only be
reached after a further follow-up of 6 to 12 months.
These facts highlight the utility of the ACE in the
early diagnosis of dementia.
Differentiating AD and FTD at an early stage with
the ACE. Predicting the type of dementia that patients will eventually develop is often difficult early
in the course of the disease. We are unaware of any
other bedside instrument capable of differentiating
patients at an early stage of dementia. On the ACE,
the patients with FTD performed better on tests of
orientation and episodic memory, whereas the patients with AD did relatively better on verbal fluency
and language, consistent with the known neuropsychological profiles of the two disorders.12,13,17,47 Based
upon this pattern of performance, we devised the
VLOM ratio to differentiate AD and FTD. To illustrate this point, consider the example of a patient
presenting to a typical memory clinic in which the
prevalence rate of AD is around 40% and FTD is
lower, at 10%. If the patient has a VLOM ratio 3.2,
then the probability of AD is 76% and if the ratio is
3.2, then the probability of not having AD is about
83%. If the patients VLOM ratio is 2.2, then the
probability of FTD is 71% and conversely, if the ratio
is 2.2, then FTD can be excluded with 95% certainty. It is evident that the confidence with which a
diagnosis of AD (or FTD) can be made, or excluded,
depends on the prevalence rate of AD (or FTD) in the
population in question. The predictive values of different cut-offs for different prevalence rates can be
found at www.neurology.org. Although not infallible,
an objective and simply calculated index such as the
VLOM ratio will be helpful in prognosticating and
planning future management of patients.
Applications of the ACE. When screening an atrisk population for dementia, a test instrument
should have a high sensitivity for mild dementia as a
missed diagnosis can delay implementation of useful
social and pharmacologic interventions. At a specificity of 71%, a cut-off score of 88 on the ACE offered a
high sensitivity of 93%. At a dementia prevalence
rate of 40% (such as in a memory clinic) a very high
proportion (68%) of those who screen positive will
have dementia and 94% of those who score above the
cut-off will not. The lower cut-off score of 83 might be
more appropriate for research studies or therapeutic
trials, which require a high specificity, or when
screening populations with a low base rate of dementia. At a sensitivity of 82%, a cut-off score of 83 had a
high specificity of 96%. In a population with a 10%
dementia prevalence rate, 69% of those who fail the

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test will eventually meet diagnostic criteria for dementia, and only 2% of those with dementia will
escape detection.
The influence of age, gender, education, and cultural background on the ACE and the MMSE needs
further evaluation. In our patient sample, age, number of years of education, or gender did not influence
the predictive outcome using the ACE, but both age
and gender influenced the predictive outcome using
the MMSE.
Alterations in personality and behavior are wellrecognized features of early FTD.48 There are, however, no reliable patient-based measures of behavior.
We deliberately avoided carer-based measures in our
instrument with the intention of designing a brief
objective test. Although sensitive to early dementia
on its own, the ACE may prove even more useful
when used in combination with carer-based instruments for behavior, such as the Neuropsychiatric
Inventory.19
Limitations and future directions. The problem
of false positive diagnosis with the higher cut-off
score on the ACE is likely to be more apparent than
real in this study. Early AD patients are typically
only amnestic11 and do not fulfill the DSM-IV criteria
for dementia. However, they often fail on the ACE
because of the deliberately large weighting (35 of the
100 points) toward memory. Patients with other isolated cognitive deficits, such as aphasia, which occur
in early FTD, are also likely to appear as false positives on the ACE. In our sample, three of the seven
patients receiving a false positive diagnosis on the
ACE had FTD and all three had progressive nonfluent aphasia.
The ACE requires more time than the MMSE to
complete but rarely takes in excess of 15 to 20 minutes, except in very demented subjects. It is most
useful, however, in patients with early and mild dementia. The loss in brevity is offset by a gain in the
sensitivity for early dementia and being able to predict the type of dementia. Although the ACE is superior to the MMSE, a comparison with independent
batteries such as the AD Assessment ScaleCog49
and the Dementia Rating Scale8 will be valuable.
Our results apply to a clinic-based patient population, age 44 to 88 years, with predominantly degenerative dementia. The applicability of the ACE in the
community requires investigation. The inter-rater
and intrarater reliability of the ACE could not be
evaluated in this retrospective analysis, but as the
ACE assesses cognitive functions in an objective
manner the rater related bias is likely to be low.
The index for differentiating AD from FTD
(VLOM ratio) is derived using a sample population
that is relatively large (n 100). Nevertheless, these
findings clearly need to be replicated in an independent and prospectively studied sample.

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A brief cognitive test battery to differentiate Alzheimer's disease and frontotemporal

dementia
P.S. Mathuranath, P.J. Nestor, G.E. Berrios, et al.
Neurology 2000;55;1613-1620
DOI 10.1212/01.wnl.0000434309.85312.19
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