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Research report

Working memory, attention, and executive function inAlzheimer’s disease and frontotemporal dementia

Cheryl L. Stopford*, Jennifer C. Thompson, David Neary, Anna M.T. Richardson andJulie S. Snowden

Cerebral Function Unit, Greater Manchester Neuroscience Centre, Salford Royal NHS Foundation Trust and Clinical Neurosciences

Research Group, University of Manchester, UK

a r t i c l e i n f o

Article history:

Received 8 March 2010

Revised 21 May 2010

Accepted 7 December 2010

Action editor Sergio Della Sala

Published online 21 December 2010

Keywords:

Alzheimer’s disease

Working memory

Executive function

Attention

Phenotypic variation

Abbreviations: AD, Alzheimer’s disease; Femission computed tomography.* Corresponding author. Cerebral Function U

M6 8HD, UK.E-mail address: cheryl.stopford@manche

0010-9452/$ e see front matter ª 2010 Elsevdoi:10.1016/j.cortex.2010.12.002

a b s t r a c t

Working memory deficits are a recognised feature of Alzheimer’s disease (AD). They are

commonly ascribed to central executive impairment and assumed to relate to frontal lobe

dysfunction. Performance failures on standard tests of attention and executive function

reinforce this interpretation. Nevertheless, early-onset AD patients do not show the frank

behavioural changes indicative of frontal lobe dysfunction, and the characteristic functional

neuroimaging changes are in posterior hemispheres rather than frontal lobes. We explored

this anomaly through a comparison of working memory, attention and executive test

performance in patients with AD (a ‘typical’ early-onset group with deficits in memory,

language and perceptuospatial function and an ‘amnesic’ group) and frontotemporal

dementia (FTD). Typical-AD and FTD patients both showed impaired performance, whereas

amnesic-AD patients performed well. Despite similar quantitative performance measures,

typical-AD and FTD patients showed qualitatively distinct performance profiles. Impair-

ments inFTDpatientswere interpreted in ‘frontal’ executive termsasdeficits inattention, set

shifting and response inhibition. AD patients’ performance appeared to be influenced by

information load andwas interpreted in terms ofworkingmemory capacity. In keepingwith

these different interpretations, neuroimaging showed characteristic frontal lobe abnor-

malities in FTD and temporoparietal change in typical-AD. The findings highlight the

importance of the posterior hemispheres inworkingmemory and point to a need for caution

in the automatic attribution of working memory, attention and executive test failures to

frontal lobe failure. They underline also the phenotypic variation within AD.

ª 2010 Elsevier Srl. All rights reserved.

1. Introduction 2000; Welsh et al., 1991). It typically manifests as impair-

Memory dysfunction is a core, defining characteristic of

Alzheimer’s disease (AD) (McKhann et al., 1984; Perry et al.,

TD, Frontotemporal dem

nit, Greater Manchester N

ster.ac.uk (C.L. Stopford).ier Srl. All rights reserved

ment in episodic memory (Huff et al., 1987; Perry et al., 2000),

but may also include problems in semantic memory (Greene

and Hodges, 1996; Hodges and Patterson, 1995; Hodges et al.,

entia; MRI, Magnetic resonance imaging; SPECT, Single photon

euroscience Centre, Salford Royal NHS Foundation Trust, Salford

.

c o r t e x 4 8 ( 2 0 1 2 ) 4 2 9e4 4 6430

1992; Lambon Ralph et al., 2003; Salmon et al., 1999), and

working memory (Baddeley et al., 1986, 1991b; Becker, 1988;

Kopelman, 1985; Miller, 1973; Morris, 1986; Morris and

Baddeley, 1988). It is recognised that working and long-term

memory impairments are dissociable in AD (Baddeley et al.,

1991a; Becker, 1988; Morris and Baddeley, 1988; Stopford

et al., 2007). Moreover, there is evidence that these distinc-

tions may have neurobiological relevance. In a study of over

500 AD patients referred to a specialist early-onset dementia

clinic (Snowden et al., 2007) we showed that patients pre-

senting with a dense yet relatively circumscribed classical

amnesia (labelled amnestic AD and accounting for 10% of

cases) were older and more likely to carry apolipoprotein

(ApoE) 34 alleles than those presenting with a constellation of

cortical symptomatology, which included working memory,

language and perceptuospatial deficits (labelled “typical” AD

on the basis that they accounted for 61% of cases). The ApoE 34

allele was also significantly more common in amnestic AD,

a clearly pathological group recognised in recently proposed

research criteria (Dubois et al., 2007), than in patients with

mild memory loss who fulfil criteria for mild cognitive

impairment (MCI). Such findings highlight the importance of

careful characterisation of individual patients, including the

precise nature of memory symptoms.

The basis of working memory deficits in AD is of particular

interest. In a factor analytic study of neuropsychological

profiles in early-onset AD (Stopford et al., 2008), we found that

tasks that place demands on working memory, such as digit

reversal, spelling, and calculation, loaded onto the ‘language’

factor, rather than onto factors representing the domains of

memory or executive function. Moreover, in such early-onset

patients, we have demonstrated links between working

memory problems, language impairment and functional

imaging changes in temporoparietal regions (Snowden et al.,

2007; Stopford et al., 2007, 2008). There was no relationship

between working memory deficits and frontal lobe abnor-

malities on clinical Single photon emission computed

tomography (SPECT) imaging (Stopford et al., 2007).

Such findings appear to conflict with prevailing views. The

most influential model of working memory, developed by

Baddeley (Baddeley et al., 1986; Baddeley and Hitch, 1974),

proposes the existence of a central executive, an attentional

component that has a coordinating and supervisory role over

the two slave systems, the phonological loop, responsible for

temporary storage and rehearsal of verbal information, and

the visuospatial sketchpad, for maintenance of visual and

spatial information. Later revision of the model (Baddeley,

2000) incorporates an episodic buffer, a temporary storage

system capable of integrating information from different

sources, purported to act as the interface between working

and episodic memory. Commonly, central executive impair-

ment is thought to play a major role in AD patients’ working

memory problems. Failure to carry out two tasks concurrently

is taken as evidence of this (Baddeley et al., 1991a, 1991b, 1986;

Belleville et al., 2007; Logie et al., 2004; Morris, 1984, 1986;

Morris and Baddeley, 1988). As component tasks are titrated

for individuals’ capabilities it is argued that failure is not

simply reflective of increased cognitive load, but rather

a deficit in the central executive component of working

memory (Baddeley et al., 1986).

Executive and supervisory aspects of cognition are known

to be linked to the function of the frontal lobes (e.g., Stuss and

Benson, 1984). Although some caution has been expressed

surrounding a direct relationship (Baddeley, 1996a, 1996b;

Baddeley and Wilson, 1988), the term ‘dysexecutive’ almost

invariably holds ‘frontal’ connotations. The central executive

component of working memory too is thought to be the

preserve of frontal regions (D’Esposito et al., 1995; Muller and

Knight, 2006).

AD patients frequently demonstrate deficits on a range of

standard tests of executive function and attention (e.g.,

Baddeley et al., 2001; Belleville et al., 2007; Belleville et al.,

2006; Collette et al., 1999b; Lafleche and Albert, 1995; Nedjam

et al., 2004; Perry et al., 2000). They perform poorly on tests

of planning (Lafleche and Albert, 1995), set-switching and

rule-abstraction (Nedjam et al., 2004; Perry et al., 2000), inhi-

bition (Calderon et al., 2001; Nedjam et al., 2004; Perry et al.,

2000), generation (Lafleche and Albert, 1995), and sustained,

divided, and selective attention (Baddeley et al., 2001, 1999;

Calderon et al., 2001; Perry et al., 2000). Such deficits rein-

force the notion of a core ‘frontal executive’ deficit in AD.

Indeed, some studies report similar executive performance in

AD patients and patients with prominent frontal lobe

dysfunction, such as those with frontotemporal dementia

(FTD) (Grossi et al., 2002; Nedjam et al., 2004; Pachana et al.,

1996). A natural interpretation is that such deficits in AD

reflect primary dysfunction of the frontal lobes. Some authors

even propose executive and attentional deficits as the earliest

features of AD (Perry et al., 2000), with others further sug-

gesting that executive deficits may be a predictive preclinical

feature (e.g., Albert et al., 2001).

In keepingwith a ‘frontal’ interpretation, there is substantial

evidence of frontal pathology in AD. Plaques have been shown

to accumulate at a high rate in frontal areas in AD (Morris and

Price, 2001; Price et al., 1991). In vivo visualisation of amyloid

plaques using positron emission tomography (PET) with the

Pittsburgh compound-B (PiB) tracer, has demonstrated high

amyloid burden in the frontal lobes early in the course of AD

(Klunk et al., 2004; Mintun, 2005; Rowe et al., 2007). However,

there is evidence that amyloid burden shows an inconsistent

relationship with cognitive symptoms, functional imaging and

disease severity (Rabinovici et al., 2010; Rabinovici and Jagust,

2009), suggesting that it might not be the best indicator of the

anatomical substrate of patients’ cognitive disturbance.

The characteristic changes on functional neuroimaging in

early-onset AD are in the posterior hemispheres rather than

the frontal lobes (e.g., Foster et al., 1983; Minoshima et al.,

1997; Salmon et al., 1994). Moreover, there is little indication

of a ‘frontal’ quality to patients’ clinical presentation. Behav-

iourally, patients are socially appropriate, motivated, show

good application and persistence on cognitive tasks, and are

concerned for performance accuracy. These characteristics

contrast strikingly with the behaviour of patients with

established degenerative disease affecting the frontal lobes,

namely frontotemporal dementia (FTD). FTD patients are

socially inappropriate, show economy of effort, poor persis-

tence and lack of concern for performance accuracy. Neuro-

psychological tests have been reported to discriminate poorly

between AD and FTD (Grossi et al., 2002) including tests of

executive function (Nedjam et al., 2004). Nevertheless, there

c o r t e x 4 8 ( 2 0 1 2 ) 4 2 9e4 4 6 431

are qualitative performance differences, suggesting distinct

contributions to performance failure (Thompson et al., 2005).

Features displayed in AD, such as phonological errors on

language tasks are not characteristic of FTD patients, who by

contrast make errors of perseveration, concrete thought,

misconstruction, and poor organisation.

There is already evidence that components other than

central executive dysfunction might contribute to working

memory deficits in AD. Impaired phonological processing has

been demonstrated (Belleville et al., 1996; Caza and Belleville,

2008; Collette et al., 1999a; Hulme et al., 1993), although, in

some studies, only in a subset of patients (Belleville et al.,

1996; Collette et al., 1999a), and in other studies in no

patients at all (Morris, 1984). One interpretation is that

phonological loop impairment reflectsmore advanced disease

(Collette et al., 1999a). AD patients are also known to display

deficits on immediate prose recall tests (Baddeley andWilson,

2002; Calderon et al., 2001; Chapman et al., 1997; Greene et al.,

1996; Lindeboom et al., 2002), suggesting that an episodic

buffer deficit might also contribute to patients’ working

memory problems.

The aim of the present study was to improve under-

standing of working memory, attention and executive

impairments in early-onset AD. A primary aim was to

address the potential ‘frontal’ contribution, through a direct,

novel comparison with a prototypical ‘frontal’ disorder, FTD.

The motivation was a wish to resolve anomalies as outlined

above. On the one hand, AD is clinically very different from

FTD so one might expect a priori very different patterns of test

performance on tests of working memory and attention. On

the other hand, if a major contribution to working memory

problems in AD is a central executive disorder with

a ‘frontal’ substrate, as much of the literature suggests, then

one would predict similar patterns of performance on

working memory and attention in AD compared to FTD,

albeit less severe. The inclusion of tests of working memory,

attention and executive functions in the same study is

potentially illuminating because it allows examination of

the relationship between performance across tasks in both

disease groups.

The main focus of the study were AD patients who display

a constellation of deficits in memory, language, and percep-

tuospatial functioning. Such patients are referred to hereafter

as “typical-AD” on the basis that they account for the largest

percentage of patients presenting to an early-onset dementia

clinic (Snowden et al., 2007). They may not be “typical” of an

older AD population. Amnesic-AD patients, whose perfor-

mance is characterised by severe yet circumscribed episodic

memory deficits, were included as a reference group. Such

patients were older, and may be more representative of an

older AD population. However, in keeping with our previous

work (Snowden et al., 2007) and that of others (Bondareff,

1994) which highlight age as having a highly important but

not exclusive relationship with disease presentation, age

ranges overlapped. Patients were therefore classified on the

basis of cognitive phenotype rather than age so that the labels

‘early onset’ and ‘late onset’ AD were avoided. A secondary

aim of the study was to explore the effects of amnesia per se

on performance and thereby increase understanding of the

phenotypic variation in AD.

We predicted that both typical-AD and FTD patients, but

not amnesic-AD patients would perform poorly on tests of

working memory, attention, and executive function,

compared to a healthy control group. However, we expected

that despite quantitative similarities in typical-AD and FTD,

there ought to be qualitative differences, reflecting different

underlying reasons for failure.

2. Participants

Patients were consecutive attendees at a regional dementia

clinic, who agreed to take part in the study. Diagnoses were

made by a consultant neurologist based on a detailed history

using a structured proforma designed to elicit information

about cognitive symptoms, and a full neurological examina-

tion. Diagnoses were supported by neuropsychological eval-

uation using a locally developed screening instrument,

tapping language, perceptuospatial function, praxis, memory,

and executive function, which has been found valuable in

discriminating discrete forms of dementia (see Neary et al.,

1987; Talbot et al., 1998; Thompson et al., 2005). No patient

had a history of cerebrovascular disease or showed evidence

of vascular disease on brain imaging. All patients had been

followed up for at least 1 year, confirming the progressive

nature of the disorder and exclusion of alternative diagnoses.

Participants were excluded if they had a history of alcohol

abuse or head injury. None of the patients had a fluctuating

confusional state or reported hallucinations. Neurological

examination was either normal or revealed the presence of

mild extrapyramidal signs in keeping with AD. Grasp reflexes

were reported in 27% of FTD cases. The studywas approved by

the Local Research Ethics Committee and all participants gave

written informed consent in accordance with the declaration

of Helsinki.

Classification of AD subgroups was based on characteristic

profiles demonstrated previously (Snowden et al., 2007),

determined by clinical history of symptoms obtained at initial

diagnostic assessment using a structured proforma and

performance on a locally developed neuropsychological

screening assessment.

2.1. Typical-AD group

The group comprised 20 AD patients (7 females, 13males) who

presented with a constellation of symptoms, confirmed on

cognitive testing, and fulfilled conventional criteria for AD

(McKhann et al., 1984). All patients showed a similar pattern,

with deficits in memory, language, and perceptuospatial

functioning, albeit with variable weightings of impairment

across domains, consistent with our previous work (Stopford

et al., 2008). Their mean age at the time of testing was

61 years [standard deviation (SD) 5, range 52e68], and duration

of symptoms 4.5 years (SD 2). Sixteen patients (80%) had

undergone magnetic resonance imaging (MRI) as part of their

diagnostic work-up. This revealed generalised atrophy in

8 cases (50%), localised parietal atrophy in 2 cases (13%) and no

abnormality in 6 patients (37%). Nine patients (45%) also

underwent SPECT imaging. In 6 (66%) therewas circumscribed

hypoperfusion in parietal and temporoparietal regions, in 1

Table 1 e Clinical rating of severity: Mean (SD) MMSEscores and mode (range) ratings for each group on theClinical Dementia Rating Scale.

Typical-AD Amnesic-AD FTD

MMSE/30 18 (4) 23 (4) 23 (6)

CDR overall 1 (2) 1 (2) 1 (2)

CDR memory 1 (2) 2 (2) .5 (2)

CDR orientation 1 (2) 2 (2) 0 (2)

CDR judgement and

problem solving

1 (2) 1 (2) 2 (3)

CDR community affairs 1 (2) 1 (1) 2 (1)

CDR home and hobbies 1 (2) 1 (2) 3 (2)

CDR personal care 0 (1) 0 (1) 2 (3)

c o r t e x 4 8 ( 2 0 1 2 ) 4 2 9e4 4 6432

(11%) hypoperfusion in the medial temporal regions, and in 2

(22%) no change. Fourteen patients completed the full

protocol.

2.2. Amnesic-AD group

The group comprised 18 AD patients (10 females, 8 males),

who presented with amnesia, confirmed by neuro-

psychological assessment, but without historical evidence of

other cognitive impairment. Patients were included only if the

amnesia was of sufficient severity to be clearly pathological,

consistent with recently proposed revised criteria for AD,

which cites significant episodic memory impairment as an

early independent clinical diagnostic feature (Dubois et al.,

2007). The patients demonstrated loss of functional indepen-

dence, and could no longer work or go out alone without

getting lost. They showed reduced insight into their memory

problems. This pattern contrasts with that of MCI, charac-

terised by subjective complaints of poor memory and preser-

vation of activities of daily living (Petersen, 2004). Their mean

age at testing was 70 years (SD 7.5, range 59e83), which is

significantly older than the typical-AD group ( p¼ .02), and is

in keeping with earlier reports of clinical phenotypic influ-

ences on age at onset (Snowden et al., 2007). Mean duration of

symptoms was 4 years (SD 2), which does not differ from that

of the typical-AD group. Fourteen patients (78%) had under-

gone MR imaging. Of these, 4 (28%) demonstrated circum-

scribed temporal atrophy, in 1 (7%) restricted to medial

temporal regions. Four (29%) showed generalised atrophy and

6 (43%) had normal scans. Eleven patients (61%) also under-

went clinical SPECT imaging. Seven (64%) showed circum-

scribed temporal hypoperfusion and 4 (36%) no abnormality.

Twelve amnesic-AD patients completed the full protocol.

2.3. FTD patients

The group comprised 26 FTD patients (13 males, 13 females).

All had a history of behavioural and cognitive changes and

fulfilled published criteria for FTD (Neary et al., 1998; The Lund

and Manchester Groups, 1994). Patients with alternative

syndromes of frontotemporal lobar degeneration (semantic

dementia, primary progressive non-fluent aphasia) were not

recruited. Mean age at test was 64 years (SD 6), and duration of

illness 6 years (SD 3.5), which was not significantly different

from that of the AD groups. Twenty patients (77%) underwent

MR imaging. Eight (40%) showed frontal and temporal atrophy,

3 (15%) frontal, and 4 (20%) temporal. In 3 cases (15%) atrophy

was generalised, and in 2 (10%) scans were normal. Fifteen

patients (58%) underwent clinical SPECT imaging. Eight (53%)

showed frontotemporal hypoperfusion, 4 (27%) circumscribed

frontal and 1 (7%) temporal hypoperfusion. Two (13%) showed

no abnormalities. Thirteen FTD patients completed the full

protocol.

2.4. Controls

The group comprised 26 healthy controls (18 females, 8

males), who were relatives of patients attending the diag-

nostic clinic and were matched to the patient groups with

respect to socio-economic and educational background. Mean

age at test was 59 years (SD 13.5), which is significantly

younger than the amnesic-AD group ( p< .001), but not other

patient groups. Sixteen controls completed the full protocol.

2.5. Severity of symptoms

Severity was rated for each patient using the Clinical Dementia

Rating Scale (CDR). The mode and range for each group is

shown in Table 1. Overall, patients were rated to be in the mild

stages of their disorder, although there was differential

weighting of impairment in the groups, with the amnesic-AD

group rated worse on memory and orientation measures, and

the FTD group on judgement and problem solving, community

affairs, home and hobbies, and personal care. Despite their

lower scores onMiniMental State Examination (MMSE) testing,

the typical-AD participants were rated asmildly impaired in all

categories.

2.6. Background neuropsychology

A range of background neuropsychological tests were

administered at the time of experimental testing, illustrating

the differences in profile. Tests includedmeasures of language

(Manchester word-picture matching and naming tests), per-

ceptuospatial skills [Visual Object and Space Perception

battery (Warrington and James, 1991)], memory (orientation,

memory for a story), and executive functions [category and

letter fluency, Weigls blocks’ task (De Renzi et al., 1966)].

The typical-AD group performed poorly across the range of

tasks (Table 2), whereas the amnesic-AD group was impaired

on memory tasks only. Formal memory performance in the

two AD groups was comparable. The amnesic group showed

numerically larger proportional information loss from

immediate to delayed story recognition, but statistical

comparison of the two groups did not reach significance

( p¼ .24). FTD patients also showed memory impairment.

However, whereas the AD groups showed both recall and

recognition impairment, deficits in FTD were restricted to

recall. Moreover, there was no abnormal loss of information

over a delay. Predictably, FTD patients were impaired on tests

known to be sensitive to frontal lobe function: category and

letter fluency and Weigls’ block sorting. The typical-AD group

also showed impairment on these tests. However, persever-

ative responses, a salient marker of frontal lobe dysfunction,

Table 2 e Background neuropsychological test performance.

Typical-AD mean (SD) Amnesic-AD mean (SD) FTD mean (SD) Controls mean (SD)

Comprehension: Word-picture match/40 40 (1) 40 (0) 40 (1) 40 (0)

Naming: Word-picture match/40c 34 (4)a 40 (2) 35 (6)a 39 (1)

VOSP shape detection/20c 18 (1)a 19 (1) 18 (2)a 20 (1)

VOSP incomplete letters/20d 12 (7)a 19 (1) 18 (4) 19 (1)

VOSP dot counting/10d 8 (3)a 10 (0) 9 (2) 10 (0)

VOSP position discrimination/20c 17 (5)a 20 (1) 18 (2) 20 (0)

Temporal orientation/5 3 (1)a 3 (2)a 4 (2)a e

Place orientation/5 3 (1)a 4 (1)a 4 (1)a e

Story immediate recall/10d 3 (2)a 4 (2)a 5 (3)a 8 (1)

Story immediate recognition/10d 7 (2)a 8 (2)a 9 (5) 10 (1)

Story delayed recall/10d 1 (2)a 1 (1)a 5 (4)a 9 (1)

Story delayed recognition/10d 5 (3)a 4 (3)a 8 (2) 10 (1)

Story recall proportion retained (%)d 40 (61)a 40 (62)a 92 (44) 112 (18)b

Story recognition proportion retained (%)d 75 (24)a 59 (41)a 93 (14) 99 (3)

Category fluency (Animals)d 10 (4)a 15 (4) 12 (8)a 21 (7)

Letter fluency (FAS total)d 18 (9)a 33 (14) 24 (19)a 42 (11)

Weigls blocks/9c 6 (3)a 9 (1) 6 (4)a 9 (0)

Weigls perseveration (% of group)c 0 (0) 8 (27) 32 (48)a 0 (0)

a Scores indicate significant difference from control performance.

b In ‘proportional retention’ figures, delayed recall and recognition are expressed as a percentage of immediate recall and recognition; figures

are greater than 100 when the amount of information produced after a delay exceeds that produced on immediate recall/recognition.

c Group difference significant at the p< .05 level.

d Group difference significant at the p< .001 level.

c o r t e x 4 8 ( 2 0 1 2 ) 4 2 9e4 4 6 433

were absent in typical-AD, contrasting with their high

frequency in FTD.

3. Methods

The experimental investigations fall into three broad cogni-

tive domains: working memory, attention, and executive

function. These are considered separately below. Tasks were

presented in a set order (session one: simple vigilance,

continuous performance, set-switching; session two: modi-

fiedworkingmemory test, go-no-go, visual patterns, body part

pointing, phonological similarity effect, word length effect),

designed to prevent fatigue and reduce interference during

the two separate hour-long testing sessions. Instructionswere

designed to be as concise as possible and were repeated and

explained as required. Breaks were provided as necessary. In

addition to recording test responses, observations of patients’

behaviour (e.g., compliance, effort, attentiveness, persistence,

distractibility, impulsivity) were made during assessments in

accordance with our standard clinical practice, since such

qualitative factors have relevance for understanding patients’

performance (Thompson et al., 2005).

3.1. Working memory

3.1.1. Modified working memory taskThis version of the BrownePeterson paradigm (Peterson and

Peterson, 1959) has been described in detail elsewhere

(Stopford et al., 2007). This modification involves three

conditions: (i) No distraction, no delay: recall of three mono-

syllabic words immediately after reading them aloud; (ii) No

distraction, with delay: recall of three words following a 5-sec

unfilled delay; (iii) With distraction, with delay: recall of three

words following a filled 5-sec interval of number reading. Six

trials of each condition were split into two halves and pre-

sented in a counter-balanced order. The primary outcome

measure was the number of words recalled in each condition.

3.1.2. Digit span forwards and reverseDigits were presented orally at a rate of 1 digit/sec and partici-

pants were asked to repeat the digits in the same order in the

forwards task, or in reverse order in the reversal task. Testing

beganwith twodigits andtwo trialswerepresentedat eachspan

size to amaximumof 9 digits. Testingwas terminatedwhen the

participant failed both trials. Error frequency analyses were

carried out to examine the proportion of sequencing, omission,

commission and substitution errors committed on the task.

3.1.3. Body part pointing testParticipants were asked to point to four body parts (nose,

shoulder, wrist, chin), and then to point to the same body

parts in a prescribed order. Error frequency analyses were

carried out to examine sequencing and omission errors.

3.1.4. Phonological similarity effect testSeparate pools of seven phonologically similar and dissimilar

letterswere constructed. The similar letter set comprised: B, C,

D, G, P, T, V; and the dissimilar letters were F, H, L, J, Q, R, M.

Letters were taken from each set and randomly sequenced to

create the repetition stimuli. The similar and dissimilar sets

were tested separately, with similar sets presented first.

Letters were read aloud at a rate of 1.5 sec per letter and

participants were asked to repeat them immediately, in the

same order as presented. A short practice trial of two letters

preceded testing to ensure understanding of the instructions.

Testing began with two letters, and three trials were pre-

sented at each span length to amaximum of 7 letters. The test

c o r t e x 4 8 ( 2 0 1 2 ) 4 2 9e4 4 6434

was discontinued when the participant failed all three trials.

The primary outcome measure was letter span, in the

phonologically similar and dissimilar conditions.

3.1.5. Word length effect testThe stimuli and procedure of the word length effect test were

based on those used by Belleville et al (1996). Two sets of nine

words were constructed, from which to compile word series for

repetition. One set consisted of short (monosyllabic) words: bag,

chain, draw, fun,meat, salt, phone, pick, tree. The other consisted of

long (four syllable) words: academic, automobile, competition,

discovery, emergency, institution, machinery, television, emotional.

Wordswere generatedusing theMedical ResearchCouncil (MRC)

Psycholinguistics Database (Wilson, 1988) andwerematched for

KuceraeFrancis frequency, imageability, and familiarity. Words

were taken from each set and randomly sequenced to create the

repetition stimuli. Short and long words were tested separately,

with shortwords tested first.Word sequenceswere readaloud to

participants at a rate of 1.5 sec per word, and participants were

asked to repeat them immediately in the same order. Prior to

testing, the words were read aloud to the participants for famil-

iarisationandashortpracticetrialof twowordswascompletedto

ensure comprehension of the instructions. The test began with

repetition of two words, and three trials were presented at

increasing span length (maximum 7 words). The test was dis-

continuedwhentheparticipant failedall threetrials.Theprimary

outcome measure was word span, in the short word and long

word conditions.

3.1.6. Visual patterns test (Della Sala et al., 1997)In this test of visual short-termmemory, participants are shown

a ‘checkerboard’ style grid and asked to remember a pattern of

filled and unfilled squares. After 3 sec the grid is covered and

participants are asked to reproduce the pattern by shading

squares onablankgridof the samedimensions. Itemsare scored

correct if the pattern is reproduced without error. The grids

increase in number of filled and empty squares over successive

trials, with three trials at each level of complexity. The test was

discontinued when the participant failed all three trials. The

primary outcome measure was the maximum number of filled

squares accurately recalled (i.e., the level of complexity reached).

For this study, prior-test familiarisation items involving grids of 2

squaresweredevelopedas somepatientswereoverloadedby the

demands of the published practice items.

3.2. Attention

3.2.1. Vigilance task A: simple sustained attention taskDuring this sustained attention task, participants viewed

a computer monitor upon which was displayed a central

fixation box. Participants were instructed to press a response

key as quickly as possible whenever a number (always 3)

appeared inside the fixation box. A total of 54 targets were

presented for 300 msec at intervals of 2800, 5800 or 8800 msec.

The intervals were presented in random order within blocks

in which each interval type occurred once, thus enabling

comparison of time periods. The full test ran for 6 min. A short

practice trial preceded the test to ensure comprehension of

the instructions. Outcome measures were reaction time (RT),

and number of targets accurately detected.

3.2.2. Vigilance task B: continuous performance testParticipants viewed a computer monitor upon which was

displayed a central fixation point (þ). Digits from 0 to 9 were

presented for 300 msec at ‘fast’ (1500 msec) or ‘slow’

(3500 msec) intervals. Participants were instructed to press

a response key as quickly as possible whenever the number 3

was displayed. The ratio of targets to non-targets was 1:2.

Three ‘fast’ and three ‘slow’ blocks were alternated (f/s/f/s/f/s)

during the test, which ran for 10 min. A short practice trial was

administered prior to testing to facilitate familiarity with the

task and stimuli. Primary outcome measures were RT to

detect targets and the number of targets accurately detected.

3.2.3. EquipmentFor the computerised tasks, stimuli presentation and

response collection were controlled by E-Prime (Psychological

Software Tools, Pittsburgh, PA) using a 19-inch TFT display.

3.3. Executive function

3.3.1. Inhibition: go-no-go taskParticipants viewed a computer monitor on which was dis-

played a central fixation point (þ). Digits from 0 to 9 were

presented for 300 msec at intervals of 1500 msec. In contrast

to the vigilance tasks, participants were instructed to press

a response key to every number (‘go’ trials) except the number

‘3’ (‘no-go’ trials). Responses were accepted as valid up to

1000 msec after stimulus presentation. The test was split into

6 blocks, separated by short breaks. Forty-five stimuli were

presented in each block and the ratio of ‘go’ and ‘no-go’

stimuli varied as follows:

1:1 22 no-go: 23 go

1:3 11 no-go: 34 go

1:8 5 no-go: 40 go

Two blocks of each ratio patternwere presented in random

order. The primary outcome measure was the error rate

(number of errors made/number of errors possible per ratio

condition). Both inhibition (failure to inhibit a ‘no-go’

response) and omission (failure to respond to a ‘go’ target)

errors were recorded.

3.3.2. Mental flexibility: set-switching taskParticipants viewed a computer monitor upon which pairs of

stimuli were presented. Pairs of stimuli consisted of coloured

shapes (blue square, red square, blue circle, red circle), and in

each pair, items were matched by one dimension but not the

other (e.g., shape: blue circle, red circle; colour: red square,

red circle). Twelve stimuli combinations were produced.

Participants were instructed to choose a dimension to attend

to and to verbally state whether the items were the same or

different according to that feature. They were told that

occasionally the dimension would change and they would be

expected to identify the change and adjust their responses

accordingly. Their initial response was treated as correct and

fixed the first response dimension (i.e., if they responded

‘same’ when the stimuli were the same colour, ‘colour’ was

set as the target dimension). Following six consecutive

c o r t e x 4 8 ( 2 0 1 2 ) 4 2 9e4 4 6 435

correct responses the target dimension was shifted.

Although they were not warned of the change, positive

(green tick) and negative (red cross) feedbacks were given,

and they were instructed to use this to inform their

responses. The stimuli remained visible until a response was

made. The examiner pressed the response buttons on the

keyboard in order to reduce output demands. A total of 48

stimuli were presented in random order. The computerised

task was preceded by an initial abstraction task in order to

familiarise participants with the stimuli and concepts

involved in the test. Sets of stimuli (e.g., two blue circles)

were presented and participants were asked to explain how

they were the same. Participants were encouraged to use the

word ‘shape’ and ‘colour’ in their responses in order to

highlight the importance of these dimensions in this task.

The primary outcome measures were the number of

dimension shifts achieved, RTs per dimension shift (i.e.,

amount of time taken to achieve six consecutive responses),

and RTs at dimension shift changeover.

4. Results and discussion

4.1. Working memory

Performance on tasks of workingmemory is shown in Table 3.

4.1.1. Modified working memory taskA group� condition (4� 3) repeated measures analysis of

variance (ANOVA) revealed a main effect of group [F(3, 61)¼27.05, p< .001] and condition [F(2, 122)¼ 37.05, p< .001] and

a significant interaction effect [F(6, 122)¼ 6.36, p< .001]. The

typical-AD group performed significantly worse overall than

all other groups ( p< .001). The FTD group was also impaired

compared to controls ( p¼ .013).

Table 3 e Mean scores on working memory tasks.

Test Condition Typ

Modified working memory No delay

No distraction (/18)

13

With delay

No distraction (/18)

11

With delay

With distraction (/18)

7

Digit span Forwards 5

Reverse 3

Omission errors 2

Sequencing errors 1

Comission errors

Substitution errors

Body parts Total/4 2

Omission errors 1

Sequencing errors

Phonological similarity effect Similar 3

Dissimilar 4

Word length effect Short 3

Long 2

Visual patterns span 3

a Scores indicate significant difference from control performance.

To determine the nature of the condition effect, separate

ANOVAs were carried out for delay and distraction. A group -

� delay (4� 2) repeated measures ANOVA revealed a main

effect of group [F(3, 61)¼ 17.33, p< .001] and delay [F(1, 61)¼13.91, p< .001], but no interaction effect [F(3, 61)¼ 2.33,

p¼ .083]. The typical-AD group performed significantly more

poorly than all other groups ( p< .001), evenwhen there was no

delay between presentation and recall [F(3, 61)¼ 9.37, p< .001].

A group� distraction (4� 2) repeated measures ANOVA

revealed a main effect of group [F(3, 61)¼ 27.94, p< .001] and

distraction [F(1, 61)¼ 33.42, p< .001], and a significant group -

� distraction interaction [F(3, 61)¼ 5.97, p¼ .001]. The typical-

AD group performed significantly more poorly than all other

groups ( p< .001). The FTD group performedmore poorly than

controls on the distraction task only ( p¼ .005). An ANOVA of

percent reduction in score with distraction showed that

distraction had a more deleterious effect on the typical-AD

group than other groups [F(3, 61)¼ 8.38, p< .001]; (post-hoc

Bonferroni comparisons: FTD: p¼ .045; amnesic-AD: p¼ .002;

controls: p< .001).

4.1.2. Digit spanANOVAs of group� digit span forward [F(3, 66)¼ 7.86, p< .001]

and group� digit reversal [F(3, 66)¼ 6.21, p¼ .001] tasks

showed the typical-AD and FTD groups to have a reduced span

relative to controls at the p< .05 level.

Analysis of errors in typical-AD and FTD revealed that the

FTD groupmademore sequencing errors on both the forwards

task [F(1, 33)¼ 5.21, p¼ .029] and the reversal task [F(1, 33)¼4.51, p¼ .042]. The two groups did not differ with respect to the

number of omission, commission or substitution errors.

4.1.3. Body parts taskThe typical-AD group performed worse than all other groups

in pointing to a sequence of body parts ( p< .05). The control

ical-AD Amnesic-AD FTD Control

.9 (4.7)a 17.9 (.3) 16.9 (2.6) 18.0 (.0)

.9 (4.1)a 17.3 (.8) 15.8 (2.9) 17.9 (.2)

.3 (5.2)a 17.0 (.7) 13.2 (5.3)a 17.4 (.9)

.1 (1.1)a 6.1 (.8) 5.9 (3.8)a 7.1 (1.2)

.1 (1.2)a 4.1 (1.3) 3.8 (1.6)a 5.2 (1.4)

.1 (1.6) 1.6 (1.2) 1.4 (1.1) 1.7 (1.3)

.7 (1.4) 3.1 (1.6) 3.0 (1.4)a 2.6 (1.5)

.5 (.8) .5 (.6) .4 (.6) .2 (.4)

.9 (.8) .6 (1.1) .5 (.7) .4 (.6)

.5 (1.1)a 3.9 (.2) 3.4 (1.1) 4.0 (.0)

.3 (1.0)a .0 (.0) .3 (.9) .0 (.0)

.1 (.3) .1 (.2) .4 (.7) .0 (.0)

.8 (1.1)a 4.2 (1.0) 4.1 (1.0)a 4.6 (.6)

.3 (1.3)a 5.7 (1.1) 4.9 (.8)a 6.0 (.9)

.9 (1.0)a 5.8 (.9) 5.2 (1.0) 5.7 (.9)

.5 (.8)a 3.9 (.6) 3.9 (1.3) 4.7 (1.0)

.7 (2.4)a 6.3 (2.0) 5.0 (2.2)a 7.5 (1.3)

c o r t e x 4 8 ( 2 0 1 2 ) 4 2 9e4 4 6436

and amnesic-AD groups perform at or near ceiling on this task

and were not included in the error analysis.

Typical-AD patients made more omission errors than FTD

patients [F(1, 33)¼ 9.58, p¼ .004]. FTD patients show a numer-

ically higher frequency of sequencing errors than typical-AD

participants, although this difference did not reach statis-

tical significance [F(1, 33)¼ 3.23, p¼ .082].

4.1.4. Phonological similarity effect testA group� phonological similarity (4� 2) repeated measures

ANOVA revealed significant main effects of group [F(3, 59)¼8.04, p< .001] and phonological similarity [F(1, 59)¼ 69.65,

p< .001], and a significant group� phonological similarity

interaction [F(3, 59)¼ 3.86, p¼ .014].

The typical-AD group performed more poorly than both

controls ( p< .001) and the amnesic-AD group ( p¼ .030). The

FTD group was also impaired compared to controls ( p¼ .022).

The typical-AD and FTD groups did not differ significantly.

As expected, phonologically similar letters yielded poorer

repetition performance than dissimilar letters. The similarity

effect was statistically significant in the amnesic-AD (t¼�5.0,

p< .001), FTD (t¼�2.7, p¼ .018) and control (t¼�7.7, p< .001)

groups but not in the typical-AD group (t¼�2.0, p¼ .068).

4.1.5. Word length effect testA group�word length (4� 2) repeated measures ANOVA

revealed main effects of group [F(3, 60)¼ 18.37, p< .001] and

word length [F(1, 60)¼ 115.74, p< .001]. The interaction of

group�word length failed to reach statistical significance

[F(3, 60)¼ 2.73, p¼ .052].

The typical-AD group performedmore poorly than all other

groups ( p< .001), indicating a reduced overall word span.

Performance in amnesic-AD and FTD groups was comparable

to that of controls (amnesic-AD vs control: p¼ 1.000; FTD vs

control: p¼ .134). Shorter words elicited a longer word span

than longer words. A significant word length effect was

evident in all groups at the p< .001 level.

4.1.6. Visual patterns testA one way ANOVA showed a significant group difference for

visual span [F(3, 60)¼ 12.96, p< .001]. The typical-AD group

demonstrated a shorter visual span than both controls

( p< .001) and the amnesic-AD group ( p¼ .005). The FTD group

also demonstrated poorer performance than controls

( p¼ .002). Performance in typical-AD and FTD groups did not

differ significantly [t(25)¼�1.46, p¼ .157].

4.1.7. DiscussionPatient performance is summarised in Table 4a. The typical-AD

group showed striking impairment of working memory.

Performance on themodified working memory task and ability

to point to four body parts in sequence was impaired. Digit,

letter, word, and visual span were reduced. Remarkably, FTD

patients too demonstrated reduced performance on all tasks

excluding word span. However there were fundamental

differences in performance characteristics. Although both

groups showed significant effects of distraction on themodified

working memory task, only the AD group showed profound

impairment evenwithout delay or distraction,whereas the FTD

group was impaired with distraction only. On span tasks, FTD

patients showed a normal phonological similarity effect,

whereas typical-ADpatientsdidnot. FTDpatientswereprone to

sequencing error, whereas omission errors were more preva-

lent in AD. Taken together, the results suggest an attentional

andexecutive substrate inFTD,andaphonological contribution

to impairment in typical-AD, with suggestion of faulty assimi-

lation, rehearsal, and/or storage. Notably, the amnesic-AD

group performed within normal limits across tasks.

4.2. Attention

4.2.1. Vigilance task A: simple sustained attention taskData were separated into three blocks to examine perfor-

mance at the beginning, middle and end of the task, for each

rate of presentation. Accuracy performance is summarised in

Fig. 1.

A 4� 3� 3 (group� block� presentation rate) ANOVA

of accuracy data revealed significant main effects of group

[F(3, 69)¼ 10.12, p< .001] and presentation rate [F(2, 138)¼21.07, p< .001], but not of block [F(2, 138)¼ .55, p¼ .581]. There

were significant interactions of group x presentation rate [F(6,

138)¼ 3.62, p¼ .002] and block x presentation rate [F(4, 276)¼2.59, p¼ .037], but not group x block ( p¼ .360) or group -

� block� presentation rate ( p¼ .207).

The FTD group missed significantly more targets than the

typical-AD group ( p¼ .003), the amnesic-AD group ( p¼ .046)

and the healthy controls ( p< .001). Performance accuracy in

the typical-AD group did not differ significantly from that of

controls.

Patient groups made more errors with faster presentation.

Paired t-tests revealed that bothADgroupsmademore errors in

the 2800msec condition than in the 5800msec (typical-AD:

p¼ .006; amnesic-AD: p¼ .047) and 8800msec conditions

(typical-AD: p¼ .015; amnesic-AD: p¼ .029). No significant

differences were observed between the 5800 msec and

8800msec conditions in the AD groups. The FTD group made

moreerrors in the2800msec ( p¼ .016) and5800msec ( p¼ .033)

conditions compared to the 8800msec condition.No significant

differences were observed between conditions for controls.

Prior to RT analysis, outliers (�2.5 SD) were removed from

individual participants’ datasets. 1.24% of data were removed.

A 4� 3� 3 (group� block� presentation rate) repeated

measures ANOVA of RT data showed no significant main

effect of group [F(3, 61)¼ 2.59, p¼ .060], or block [F(2, 122)¼ .89,

p¼ .413], but there was a significant effect of presentation rate

on RT [F(2, 122)¼ 51.17, p< .001]. RTs for the 2800 msec

presentation rate (Mean 361.2msec; SD 50.1) were slower than

those for the 5800 msec (Mean 335.8msec; SD 50.0) (t¼ 8.6,

df¼ 64, p< .001) and the 8800 msec presentation rates (Mean

332.6 msec; SD 50.0) (t¼ 7.5, df¼ 64, p< .001). There were no

significant interactions.

4.2.2. Vigilance task B: continuous performance testAccuracy performance is summarised in Fig. 2. A 4� 3� 2

(group� block� delay) ANOVA of accuracy data (accurate

target detection) showed significantmain effects of group [F(3,

65)¼ 4.29, p¼ .008], block [F(2, 130)¼ 11.74, p< .001], and

presentation rate [F(1, 65)¼ 13.72, p< .001]. Accuracy wors-

ened over the course of the test and with slower speed of

presentation. There were no significant interactions.

Table 4 e Summary table of findings.

Task Measure Result Comment

(a) Working memory

Modified working memory test Overall accuracy Typ-AD< FTD<Amn-AD¼ control Poorer performance in Typ-AD than other groups

Typ-AD impaired even without distraction or delay

FTD impaired only when distraction present

Amn-AD performance normal

No distraction, no delay Typ-AD< FTD¼Amn-AD¼ control

With delay Typ-AD< FTD¼Amn-AD¼ control

With distraction Typ-AD< FTD<Amn-AD¼ control

Digit span Forward and reverse Typ-AD¼ FTD<Amn-AD¼ control Span impaired in Typ-AD and FTD but not Amn-AD

More sequencing errors in FTDSequencing errors FTD>Typ-AD

Body part pointing Accuracy: four body parts Typ-AD< FTD<Amn-AD¼ control Poorer performance in Typ-AD than other groups

Typ-AD more prone to omission error (“forgetting” items),

FTD show tendency to misorder items

Omission errors Typ-AD> FTD

Sequencing errors FTD>Typ-AD (trend)

Phonological similarity task Overall letter span Typ-AD¼ FTD<Amn-AD¼ control Reduced letter span in both Typ-AD and FTD

Normal phonological similarity effect in FTD but not Typ-AD.Phonological similarity effect Absent in Typ-AD; Present in others

Word length Overall word span Typ-AD< FTD¼Amn-AD¼ control Reduced word span in Typ-AD only

Span affected by word length in all groupsWord length effect Present in all groups

Visual patterns Visual span Typ-AD¼ FTD<Amn-AD¼ control Reduced visual span in both Typ-AD and FTD

(b) Attention

Vigilance A: sustained attention Detection accuracy FTD<Typ-AD¼Amn-AD¼ control FTD impaired accuracy, Typ-AD perform normally

Accuracy in all patient groups affected by presentation speed

Speed of response normal in all groups

Presentation speed effect More errors with faster presentation

speed in patient groups, not controls

Reaction time Typ-AD¼ FTD¼Amn-AD¼ control

Vigilance B: continuous performance Overall accuracy Typ-AD¼ FTD<Amn-AD¼ control Typ-AD and FTD both show impaired accuracy

Response times normal in all groups

Behavioural observations show loss of track in Typ-AD

and distractibility in FTD

Reaction time Typ-AD¼ FTD¼Amn-AD¼ control

Loss of track of task Typ-AD present; FTD absent

Distractible behaviour FTD present; Typ-AD absent

(c) Executive function

Go-no-go Inhibition (no-go) errors FTD> other groups FTD make most ‘no-go’ responses and show marked effect

of ‘go’ to ‘no-go’ ratio

Both Typ-AD and FTD omit targets

Amn-AD perform normallyEffect go:no-go ratio FTD> other groups

Omission (go) errors Typ-AD¼ FTD<Amn-AD¼ controlSet-switching Accuracy FTD<Typ-AD<Amn-AD< control Impaired set-switching in all patient groups, worst in FTD

Response times slowed in Typ-AD and Amn-AD, not FTD

Typ-AD lose track, request repetition of instructions

FTD show erratic responding with poor use of feedback

Response time Typ-AD<Amn-AD< FTD¼ control

Loss of track Typ-AD present; FTD absent

Erratic, impulsive responses FTD present; Typ-AD absent

cortex

48

(2012)429e446

437

Fig. 3 e Performance on Vigilance task B, a continuous

performance task. The figure shows RT across three time

period blocks and at ‘fast’ (1500 msec) and ‘slow’

(3500 msec) rates of presentation. Error bars show

standard error of the mean.

Fig. 1 e Accuracy performance on Vigilance task A,

a simple sustained attention task. The figure shows

accuracy levels at fast (2800 msec), ‘medium’ (5800 msec)

and ‘slow’ (8800 msec) rates of presentation. Error bars

show standard error of the mean.

c o r t e x 4 8 ( 2 0 1 2 ) 4 2 9e4 4 6438

Both the typical-AD group and the FTD groups were less

accurate than controls ( p¼ .021 and p¼ .048 respectively).

Accuracy scores of the amnesic-AD group were not signifi-

cantly worse than those of the control group ( p¼ .150).

Prior to RT analysis, outliers (�2.5 SD) were removed from

individual participants’ datasets. .48% of data were removed.

Performance is summarised in Fig. 3. A 4� 3� 2 (group -

� block� delay) ANOVA of RT data revealed significant main

effects of block [F(2, 104)¼ 11.18, p< .001] and presentation

rate [F(1, 52)¼ 43.52, p< .001], but no main effect of group [F(3,

52)¼ 2.39, p¼ .079] and no interaction effects. Response times

increased over the course of the test and with slower speed of

presentation. However, there were no group differences.

4.2.3. Behavioural observationsTypical-AD participants frequently became flustered and lost

track of instructions during the continuous performance test,

despite adhering to the rules appropriately during the imme-

diately preceding practice trials. Statements such as “What

Fig. 2 e Performance on Vigilance task B, a continuous

performance task. The figure shows accuracy across

three time periods and at ‘fast’ (1500 msec) and ‘slow’

(3500 msec) rates of presentation. Error bars show

standard error of the mean.

was I looking for?” and “I’ve lost it” were common. Contrast-

ingly, FTD participants showed poor application to tasks,

becoming easily distracted, talking to the examiner, and

looking at and commenting on objects around the room. Two

FTD participants disobeyed the rules entirely after practice,

and tapped the button to a self-generated rhythm.

4.2.4. DiscussionPatient performance is summarised in Table 4b. Typical-AD

patients performed normally on the sustained attention vigi-

lance task, but showed reduced accuracy on a continuous

performance task. The only difference between the tasks was

the amount of sequential information to be processed. By

contrast, FTD patients were impaired on both tasks. Notably,

the two groups demonstrated different behavioural charac-

teristics. Whereas AD patients had difficulty holding on to test

instructions and frequently asked for them to be repeated,

FTD patients showed reduced application and distractibility.

The findings suggest that typical-AD patients are influenced

by cognitive load, whereas FTD patients demonstrate

a primary disorder of attention.

The effect of cognitive load in typical-AD cannot be

attributed to generalised cognitive slowing. Typical-AD

participants demonstrated comparable response times to

controls and other patient groups on the vigilance tasks. On

the continuous performance task, faster presentation

(1500 msec) led to faster response times and increased accu-

racy in typical-AD as in other groups. Thus, it is not speed of

information processing that is critical but processing capacity.

Notably, the amnesic-AD group performed entirely normally

across attentional tasks.

4.3. Executive function

4.3.1. Inhibition: go-no-go taskIn this task, wewere notmeasuring vigilance over time per se,

and there were rest periods between each block. Therefore

blocks of the same ratio condition were collapsed together for

analysis. Inhibition error rates (number of incorrect ‘go’

Fig. 4 e Inhibition error rate on the go-no-go task as a function of no-go:go ratio. Error bars show standard error of themean.

c o r t e x 4 8 ( 2 0 1 2 ) 4 2 9e4 4 6 439

responses to a ‘no-go’ stimuli/number of ‘no-go’ stimuli per

ratio condition) for the three ratio blocks are shown in Fig. 4.

A 4� 3 (group� ratio) ANOVA of inhibition error rate data

revealed no main effect of group [F(3, 60)¼ 1.89, p¼ .141], but

a significant effect of ratio [F(2, 120)¼ 21.73, p< .001], and

group� ratio interaction [F(6, 120)¼ 2.24, p¼ .044]. Errors

increasedas the ratioof ‘no-go’ stimuli to ‘go’ stimuli decreased,

although to a lesser degree in the AD groups compared to the

FTDand controls.Numerically, theFTDgroupmade thehighest

number of inhibition errors overall, although this did not reach

statistical significance [F(3, 60)¼ 1.34, p¼ .270].

The omission error rate (i.e., failure to respond to ‘go’

stimuli/number of ‘go’ responses possible per ratio condition)

is shown in Fig. 5.

A 4� 3 (group� ratio) ANOVA of omission error rate data

revealed main effects of group [F(3,60)¼ 8.98, p< .001], and

Fig. 5 e Omission error rate on the go-no-go task as a function of

ratio [F(2, 120)¼ 16.50, p< .001], but no significant group x ratio

interaction [F(6, 120)¼ 1.37, p¼ .239]. Errors decreased as the

ratio of ‘no-go’ to ‘go’ stimuli decreased. The typical-AD

( p< .001) and FTD ( p¼ .028) groups made more errors than

the controls. Direct comparisons of the typical-AD and FTD

groups did not reveal significant differences in omission error

rate ( p¼ .143), demonstrating that the AD participants did not

‘miss’ more ‘go’ targets than FTD participants.

4.3.2. Mental flexibility: set-switching taskResults are shown in Table 5. The groups differed in terms of

number of dimension shifts achieved [F(3, 59)¼ 9.66, p< .001].

All patient groups attained fewer correct dimension shifts

than controls (typical-AD: p< .001; amnesic-AD: p¼ .046; FTD:

p¼ .001). The groups also differed in terms of total correct

responses [F(3, 59)¼ 7.46, p< .001], all patient groups scoring

no-go:go ratio. Error bars show standard error of the mean.

Table 5 e Mean number of dimension shifts achieved, total responses correct, and total time taken to complete the set-switching task.

Typical-AD Amnesic-AD FTD Control

Dimension shifts achieved/7 2.1 (1.6)a 3.2 (1.5)a 2.3 (2.1)a 5.0 (2.0)

Total correct/40 30.2 (6.0)a 30.1 (9.2)a 26.0 (11.4)a 37.5 (4.7)

Total time (secs) 354.1 (153.0)a 205.9 (660.8)a 160.5 (405.1) 104.9 (464.9)

a Scores indicate significant difference from control performance.

c o r t e x 4 8 ( 2 0 1 2 ) 4 2 9e4 4 6440

more poorly than controls (typical-AD: p¼ .043; amnesic-AD:

p¼ .045; FTD: p< .001).

A one way ANOVA showed a main effect of group on total

RT [F(3, 59)¼ 26.74, p< .001]. The typical-AD group were

significantly slower than all other groups at the p< .001 level.

The amnesic-AD group were also slower than controls

( p¼ .006).

In order to explore this further, response times to achieve

each successive dimension shiftwere examined (Fig. 6). A 4� 7

(group� dimension shift) ANOVA revealed significant main

effects of group [F(3, 59)¼ 11.35, p< .001] and dimension shift

[F(6, 354)¼ 18.77, p< .001], and a significant dimension shift x

block interaction [F(18, 354)¼ 3.91, p¼ .002]. Response times

were slowed in typical-AD patients for early dimension shifts

but improved to normal levels over the course of the test.

4.3.3. Behavioural observationsTypical-AD participants frequently lost track of task objec-

tives and asked for repetition of instruction. They were

persistent and concerned by errors in their performance. On

the set-switching task, patients were overloaded by the task

demands. They typically ‘lost track’ of the rule before six

consecutive responses were achieved. Contrastingly, FTD

patients showed no concern for errors and appeared to

respond erratically, without regard for the rules. They made

perseverative errors. Once ‘in set’ they could sometimes

follow a rule, but there was variability as to whether they

could grasp, maintain, and shift the dimension throughout

the course of the task.

4.3.4. DiscussionPatientperformance is summarised inTable 4c.Both typical-AD

and FTD participants demonstrated difficulties on executive

Fig. 6 e Mean RTs to complete each dimension shift on the

set-switching task.

tasks, but qualitative differences arose in performance. On the

‘go-no-go’ test of inhibition, typical-AD participants omitted

both ‘go’ and ‘no-go’ responses, suggesting difficulties pro-

cessing the sequential stimuli and keeping track of instructions

rather than primary difficulties in inhibition. Failure to inhibit

responseswas not a prominent feature of performance, nor did

errors increase consistently as ratio of go to no-go stimuli

decreased. By contrast, FTD patients, who made numerically

more inhibition errors overall, showed an effect of go:no-go

ratio, pressed targets that were not to be pressed and omitted

targets that were to be pressed. Taken together, FTD patients’

performance characteristics suggest primary difficulties in

attention and inhibition of pre-potent responses.

All patient groups were impaired on the executive set-

switching task. The typical-AD group was significantly

slower than other groups in the early stages of the task, sug-

gesting problems in grasping and maintaining the task

instructions. Although speed improved during the course of

the task for those who were able to achieve 3þ dimension

shifts, some patients were unable to do so, and ‘lost track’ of

the rules. Unlike the typical-AD group, FTD patients per-

formed at a comparable speed to controls, despite their low

accuracy. Their tendency to respond quickly without regard

for accuracy implies poor adherence to the rules, with reduced

monitoring and consideration of feedback. Interestingly, the

FTD group attained a higher number of dimension shifts than

the typical-AD group but achieved fewer correct responses.

This is likely to reflect differences in response method. As

noted, typical-AD patients were easily overloaded and ‘lost

track’ of the task. Thus it was possible to attain fewer

dimension shifts, even though more ‘runs’ of correct

responses might be achieved within a single dimension. FTD

patients’ results reflect their more erratic response mode and

preponderance towards perseveration. When ‘in set’ they

were often able to achieve a dimension, but performance

varied throughout the task.

5. General discussion

The study was motivated by the body of literature that points

to the presence of workingmemory deficits in AD and the tacit

assumption that these reflect disordered frontal lobe func-

tioning. We examined this assumption by a novel, direct

comparison of AD with FTD, the prototypical “frontal lobe”

disorder. The availability of performance data not only on

working memory tasks but also on tests of attention and

executive skills provided a broader context in which to inter-

pret patients’ performance than is usually possible in working

memory studies. Moreover, the subdivision of AD patients on

c o r t e x 4 8 ( 2 0 1 2 ) 4 2 9e4 4 6 441

the basis of clinical phenotype enabled influences of amnesia

per se to be distinguished from problems of working memory.

The study confirmed earlier findings of impaired working

memory, attentionand executive taskperformance inAD (e.g.,

Baddeley et al., 1986; Baddeley et al., 2001; Baddeley et al.,

1991b; Belleville et al., 2007; Foster et al., 1999; Grady et al.,

1988; Morris and Baddeley, 1988; Parasuraman et al., 1992;

Perry and Hodges, 1999). A striking finding, however, in

comparison to some other studies is the magnitude of

impairment in working memory in the ‘typical’ youthful AD

cohort in this study, problems being demonstrated on word

repetition, even without the competing demands of

a secondary task. The findings emphasise the importance of

such deficits in the cognitive profile of AD. In stark contrast to

the typical-AD group, the reference group of amnesic-AD

patients performed for the most part entirely normally.

These group differences provide further evidence of the

dissociable components of memory in AD (Snowden et al.,

2007; Stopford et al., 2007, 2008), and highlight the fact that

the deficits seen in the typical-AD group are not an inevitable

accompaniment of classical amnesia. The distinction between

typical-AD and amnesic-AD has only rarely been made in the

literature (Snowden et al., 2007). Nevertheless, it reflects

a growing awareness that AD is clinically heterogeneous (e.g.,

Galton et al., 2000; Snowden et al., 2007; Stopford et al., 2008).

Indeed, acknowledgement of phenotypic variation is one of

themotivating factors for the revision of diagnostic criteria for

AD (McKhann et al., 2010). Phenotypic differences in clinical

cohorts might contribute to disparities in findings regarding

working memory and executive failures in AD.

The direct comparison between AD and FTD is revealing.

On working memory tasks the typical-AD group was equally

or more impaired than the FTD group, a finding not predicted

by a ‘frontal executive’ explanation. Where group differences

were present on attention and executive tasks, by contrast,

these were largely in the predicted direction of poorer

performance in FTD. There is not, therefore, a straightforward

relationship between working memory performance and

standard cognitive markers of frontal lobe function. On

working memory tasks, typical-AD patients’ difficulty even in

the absence of distraction or delay together with the

predominance of omission errors is in keeping with their self-

report of difficulty in ‘holding’ and reproducing information.

This group demonstrated even larger effects of distraction

than FTD, a finding that would be at odds with a conventional

‘frontal executive’ explanation in view of the greater clinically

overt inattentiveness and distractibility in FTD. It might,

however, plausibly be accounted for in terms of ‘information

load’. If typical-AD patients already have difficulty holding or

rehearsing information then it follows that they should be

disproportionately affected by the additional information load

involved when distraction is introduced. Moreover, the

absence of phonological similarity effects in repetition point

to a phonological, linguistic contribution to their working

memory impairment. Their deficits, symptomatic of problems

in assimilation, rehearsal, and short-term storage, differ from

those of FTD, who were impaired on the Peterson task only

when distraction was present and who made sequencing

errors on span tasks, suggesting a more dysexecutive or

attentional substrate toworkingmemory performance in FTD.

Performance on attentional tasks was consistent with this

interpretation. FTD patients were, predictably, impaired on

both simple sustained attention and continuous perfor-

mance tasks. Typical-AD patients, predictably, performed

normally on the sustained vigilance task, in line with earlier

reports (Baddeley et al., 2001; Perry et al., 2000). However,

they showed the apparently anomalous finding of impair-

ment in the novel continuous performance task, of compa-

rable magnitude to that shown in FTD. The principal

methodological difference between the two attention tasks

was the amount of information to be processed and the

inclusion of numbers other than the target increasing

cognitive load. Qualitative observations of loss of track in AD

patients, and poor engagement in FTD patients further

illustrated group differences. Cognitive load would appear to

be a crucial determining factor of performance in the AD

group, and disordered voluntary attention in FTD.

Examination of executive performance also suggested

divergent impairments in the AD and FTD groups. On the ‘go-

no-go’ test of inhibition, FTD patients produced numerically

more inhibition errors than AD, with difficulties inhibiting pre-

potent responses. One might have predicted an even higher

number of inhibition errors in FTD than actually occurred.

However, therewas variabilitywithin the FTD group. SomeFTD

patients (n¼ 5) made large numbers of inhibition errors,

whereas others (n¼ 10) were poorly engaged in the task and

producedvery fewresponsesatall,asevidencedbythehighrate

of omissions. This profile contrasted markedly with that of the

AD patients, who apparently engaged well and were keen to

succeed. Nonetheless their performance was consistent with

that in the continuous performance task, with omission of ‘go’

responses, suggesting limitations inprocessingcapacity.Onthe

set-switching task, although all patient groups were impaired,

the typical-AD group showed significant slowing in the early

stages of the task,whereas FTDpatients, despite poor accuracy,

performedatacomparablespeed tocontrols.Thismight, at face

value suggest greater impairment in typical-AD. Yet, speed of

response, we would argue, is highly relevant for precisely the

opposite reason. AD patients’ slowed initial responses are in

keeping with the clinical impression that they had difficulty

grasping and maintaining the task instructions, and took time

to attempt correct responses. By contrast, the FTD group, who

produced numerically more errors, responded quickly without

regard for feedback or error. Their lack of concern, typical of

frontal executive impairmentwas not shown by theADgroups.

In summary, although typical-AD and FTD patients both

perform poorly on working memory, attention and executive

tasks, close examination of performance suggests distinct

reasons for task failure. FTD patients show the hallmarks of

frontal executive impairment, with performance charac-

terised by inattention, poor response inhibition, and

sequencing problems. The findings in the typical-AD group, by

contrast, suggested to us a more fundamental problem of

short-term capacity: they are easily overloaded and have

difficulty holding information in short-term memory. This

difficultly in ‘holding’ on to information is very different from

the executive impairments in ‘mental set’ commonly associ-

ated clinicallywith FTD. ‘Mental set’ impairments aremanifest

clinically by irrelevant responses on tasks (e.g., the patient

namesdistractor items inaword-picturematching test instead

c o r t e x 4 8 ( 2 0 1 2 ) 4 2 9e4 4 6442

of pointing to the target picture as instructed). By contrast,

‘holding’ difficulties are manifest clinically by frequent

requests for repetition of instructions, and questions and

comments such as “what am I doing?” and “it just flies away

from me” are common. The patients in this study showed

precisely these distinctions. ADpatients asked for repetitionof

instructions and remarked that they had ‘forgotten’ what they

needed to do but remained engaged in the task. FTD patients

became disengaged, discussed irrelevant topics and required

their attention to be re-directed to the task at hand.

The findings allow us to draw the important conclusion

that poor performance on executive and attentional tasks in

AD and FTD arises for different underlying reasons. The

implication is that frontal executive dysfunction may not be

the primary basis of working memory impairment in early-

onset AD.

It is likely that there is a phonological contribution to

patients’ working memory impairment. The typical-AD group

demonstrated an abnormal phonological similarity effect,

with difficulty repeating even phonologically dissimilar

letters, consistent with their reduced span across tasks.

Notably, in previous studies we have reported phonological

errors in naming, repetition, and memory tasks (Stopford

et al., 2007; Thompson et al., 2005). Phonological short-term

memory impairments in AD have been reported by some

(Belleville et al., 1996; Caza and Belleville, 2008; Collette et al.,

1999a; Hulme et al., 1993), but not others (Morris, 1984). Such

differences have been ascribed to differences in severity of

illness (Collette et al., 1999a). Indeed, in an early study

(Kopelman, 1985) inferior performance on the Peterson para-

digm and immediate sentence recall was attributed to greater

severity of patients with more virulent disease. What is

interesting, however, is that in that study patients with

working memory problems were more youthful than those

without. Our findings (Snowden et al., 2007) suggest that

cortical temporoparietal symptomatology of impaired

language and perceptuospatial function is more usually

associated with early-onset disease. Consistent with this, the

AD patients in the present study who had working memory

impairments and reduced phonological similarity effect were

younger and more likely to show temporoparietal abnormal-

ities on neuroimaging than those amnesic-AD patients in

whom both working memory performance and the phono-

logical similarity effect were preserved. Duration of symptoms

at the time of testing was comparable in the two groups.

Moreover, all patient groupswere rated as ‘mild’ on the overall

Clinical Dementia Rating Scale and it was only in the amnesic-

AD and FTD groups that ratings on individual measures

reachedmoderate and severe levels. AlthoughMMSE scores of

the typical-AD group were lower, there is evidence to suggest

that this tool, that places heavy demands on language skills,

may be unreliable in providing a meaningful comparison of

severity among patients whose deficits are not uniform

(Stopford et al., 2008). The FTD patients in this study for

example, retain high MMSE scores despite marked behav-

ioural change and functional impairment in acts of daily

living, warranting moderate to severe scores on the Clinical

Dementia Rating Scale, a tool which is notably weighted

towards memory in its algorithm to create an overall score.

We would argue that the typical-AD patients are not simply

more severely affected, nor do they have a more virulent form

of disease, but instead that the workingmemory problems are

part of the posterior cortical symptomatology typical of

youthful presentations of AD.

The additional presence of visual span deficits points to

impairment too in visual short-termmemory. Span taskswere

carried out in isolation, therefore deficits cannot be attributed

to dual-task impairment, as has been previously argued for

other cohorts (e.g., Baddeley et al., 1991a; Baddeley et al., 1986;

Morris, 1984;Morris, 1986;Morris andBaddeley, 1988). Thedata

therefore suggest specific impairments in phonological and

visuospatial short-term capacity and processing, rather than

the central executive component ofworkingmemory.Notably,

the deficit in the typical-ADpatients bears resemblance to that

of ‘short-termmemory’ patients (e.g., Saffran andMarin, 1975;

Shallice and Warrington, 1970; Warrington et al., 1971;

Warrington and Shallice, 1969), who, like this AD cohort,

have lesions in temporoparietal cortex. These patients

demonstrate profound difficulties in auditory-verbal (e.g.,

Saffran and Marin, 1975; Shallice and Warrington, 1970;

Warrington et al., 1971; Warrington and Shallice, 1969) and

spatial (De Renzi and Nichelli, 1975) short-termmemory, with

problems in repetition span and keeping track of information

in the immediate present. Difficulties in ‘holding’ information

are reported with apparent sparing of long-term memory, in

keeping with the circumscribed temporoparietal damage and

sparing of hippocampal regions.

The connection of AD patients’ working memory impair-

ment to dysfunction of the temporoparietal regions is highly

relevant. Although the importance of the frontal lobes for

workingmemory iswell established (D’Esposito et al., 1995; Lim

et al., 2008; Muller and Knight, 2006; Peters et al., 2009), recent

years have seen an accumulation of evidence for the additional

role of posterior cortices. Studies have shown temporoparietal/

parietal activation during cross modal binding tasks (Campo

et al., 2008; Zhang et al., 2004) and memory retrieval (Berryhill

and Olson, 2008; Henson et al., 1999; Rugg et al., 2002; Simons

et al., 2008). The parietal lobes have also been shown to play

a role in information manipulation (Champod and Petrides,

2007; Marshuetz et al., 2000), temporary storage (Jonides et al.,

1998; Postle et al., 2006), and attentional networks related to

storage mediation (Magen et al., 2009). The demonstration in

healthy volunteers of activation of widespread frontoparietal

networks during working memory tasks provides further

evidence of the involvement of regions beyond the frontal lobes

(LaBar et al., 1999; Magen et al., 2009; Owen et al., 2005).

Evidence of the role of the posterior cortices in binding,

manipulation, and storage has led to the proposal that it is

these regions that correlate to the ‘episodic buffer’ component

of working memory (Vilberg and Rugg, 2008). In the present

study, typical-AD patients were easily overloaded by infor-

mation and performance declined with increased task

demands. Might this ‘overload’ of capacity reflect difficulties

in information binding, suggesting an impairment of the

episodic buffer component of working memory? Impaired

performance on associative learning tasks (Della Sala and

Logie, 2002; Lindeboom et al., 2002; Swainson et al., 2001),

difficulties holding integrated information from different

sources in verbal short-term memory (Parra et al., 2009), and

reduced benefit from semantic-relatedness in recall of word

c o r t e x 4 8 ( 2 0 1 2 ) 4 2 9e4 4 6 443

lists (Germano et al., 2008) have been reported and taken as

evidence of an episodic buffer deficit in AD. In the present

study, typical-AD patients’ impaired performance on the

continuous performance task (detecting 3s from serially pre-

sented numbers), contrasting with their preserved perfor-

mance on the sustained attention test (detecting 3s when no

non-target numbers occur) might also suggest a difficulty in

holding integrated information (i.e., respond to 3 but not to

other numbers). However there are grounds for caution.

Background neuropsychological assessment revealed

impaired immediate recall of an integrated ten-element story

in all patient groups. Both AD groups showed impaired

recognition as well as recall, indicating a failure either of

storage capacity or integration, consistent with episodic

buffer impairment. Strikingly, performance in the two AD

groups was similar. Yet, only the typical-AD patients showed

the wide ranging impairments on working memory and

attention tasks observed in this study. The typical-AD group,

whose working memory deficits were so striking that they

caused patients to lose track of tasks mid-instruction or

conversationmid-sentence, performed at a similar level to the

amnesic-AD group on prose recall. Thus an ‘episodic buffer’

deficit, although a potential contributor, cannot provide

a unitary explanation of patients’ working memory problems.

It would seem likely, then, that there are distinct contri-

butions to AD patients’ working memory disorder. To what

extent these deficits are specific to working memory or reflect

the wider contribution of non-mnestic factors, such as

impairments in language is open to question. We showed

previously through cluster analysis (Stopford et al., 2007) an

association between impairments inworkingmemory and the

presence of language and perceptuospatial deficits, suggest-

ing that working memory problems are not wholly indepen-

dent of deficits in other cognitive domains. Their precise

contribution might best be explored in a case-series analysis.

Some methodological issues warrant discussion. MMSE

scores were lower in the typical-AD group, raising the ques-

tion of differences in overall severity of illness in the groups.

However, the MMSE is known to have differential sensitivity

to different AD phenotypes (Snowden et al., 2007; Stopford

et al., 2008), and can be remarkably insensitive to the frontal

executive disorder of FTD. It does not, therefore, provide

a meaningful guide to severity of illness. Patients showed

similar overall ratings on the CDR, which provides a more

meaningful measure of functional disability. Notably, illness

duration was similar across groups, providing further

evidence that patients were at a similar stage in their illness.

Behavioural criteria were not operationally defined prior to

test administration and a formal checklist was not used,

raising the possibility of experimenter bias. Nevertheless, the

qualitative observations were documented during the course

of test administration (rather than being merely post-hoc

interpretations), and are in line with our routine clinical

practice. They are therefore considered to be valid and rele-

vant, facilitating interpretation of patients’ performance.

The imaging data presented were obtained for clinical

purposes so lack the sophisticated quantitative analysis of

experimental imaging. Moreover, they were based on selected

imaging modalities only: structural MR and functional SPECT.

There is therefore a need for caution in interpretation of

functionaleanatomical relationships. Nonetheless, images

were reported blind to clinical phenotype, so the broad

distinction between abnormalities in the frontal lobes in FTD,

temporoparietal regions in AD patients with workingmemory

problems and temporal lobes in AD patients without working

memory impairment is noteworthy.

A further limitation is the lack of confirmatory postmortem

data. Nonetheless, clinical diagnosis, determined by clinical

interview and neurological examination, and supported by

neuropsychological profiling and neuroimaging, is reliable

and accurate within this centre. In a consecutive series of 104

clinically diagnosed AD patients in whom pathological

examination has subsequently been undertaken, the diag-

nosis has been confirmed pathologically in 100% of cases. The

series includes patients exhibiting each of the clinical

presentations reported here.

In conclusion, the data highlight the prominence of

working memory deficits in early-onset AD, confirming that

they are a salient symptom of these patients, and dissociable

from the classical amnesia traditionally associated with AD.

The findings point to a need for caution in automatically

assuming that impaired performance in AD on tests of

working memory and attention necessarily implies a central

executive impairment with frontal lobe substrate. The

comparison between AD and FTD reinforces previous findings

(Thompson et al., 2005) that superficially similar quantitative

test performance may arise for qualitatively distinct reasons.

Theworkingmemory impairment cannot easily be ascribed to

a unitary functional deficit. Nevertheless, we have interpreted

the findings as consistent with defective temporary storage of

information, and suggested a primary role of the tempor-

oparietal lobes, and not the frontal lobes, in underpinning the

working memory deficits in early-onset AD. This posterior-

hemisphere hypothesis requires systematic examination.

Acknowledgements

We thank all the participants for their time and commitment

to the study. We are grateful to the Bill Edmonds Bequest for

continuing financial support.

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