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Neuropsychologia 45 (2007) 3015–3023

Universal grammar in the frontotemporal dementia spectrumEvidence of a selective disorder in the corticobasal

degeneration syndrome

Maria Cotelli a, Barbara Borroni b, Rosa Manenti c, Valeria Ginex c, Marco Calabria a,d,Andrea Moro c, Antonella Alberici b, Marina Zanetti b, Orazio Zanetti a,

Stefano F. Cappa c,∗, Alessandro Padovani b

a IRCCS, S. Giovanni di Dio-Fatebenefratelli, Brescia, Italyb Department of Neurology, University of Brescia, Brescia, Italy

c Vita Salute University and San Raffaele Scientific Institute, DIBIT Via Olgettina 58, 20132 Milano, Italyd Department of General Psychology, University of Padua, Padua, Italy

Received 6 December 2006; received in revised form 20 April 2007; accepted 29 May 2007Available online 8 June 2007

bstract

ntroduction: While sentence comprehension has been reported to be defective in frontotemporal dementia (FTD), it is still unclear if this disordereflects the presence of syntactic impairment, or may be attributed to other factors, such as executive or working memory dysfunction. In order tossess the status of syntactic knowledge in a group of patients belonging to the FTD spectrum, we investigated their ability to detect violations ofniversal Grammar principles in a sentence judgement task.ethods: The group included four semantic dementia patients (SD), nine frontal variant of FTD patients (FvFTD), 15 progressive supranuclear

alsy (PSP) patients, and 11 corticobasal degeneration syndrome (CBDS) patients. Their performance was compared to a group of 10 patients withild probable Alzheimer disease (AD) and to 10 healthy volunteers. The patients underwent a standard aphasia test and a sentence comprehension

est. The experimental study included five kinds of violations: semantic coherence (SC), verb–subject agreement (VSAgr), pronominalizationnvolving clitic movement (ClM), interrogatives (WhS) and contrastive focus constructions (CFC).esults: The FTD patients performed within normal range in the aphasia test, and in the sentence comprehension test. Within the FTD subgroups,nly patients with CBDS were significantly impaired in detecting three of the five kinds of violations. AD patients were also impaired in the

etection of WhS and SC anomalies and in sentence comprehension.iscussion: The present findings indicate that, within the FTD spectrum, an impairment of syntactic knowledge can be found only in CBDSatients, even in the absence of clinical evidence of aphasia.

2007 Elsevier Ltd. All rights reserved.

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eywords: FTD; Syntax; Comprehension; CBDS; PSP; Language impairment

. Introduction

The ability to produce and understand sentences requires theomputation of syntactic structures, and is frequently affected

y neurological damage. Typically, patients with focal brainamage involving Broca’s area show agrammatism in produc-ion (i.e. they tend to produce short, syntactically simplified

∗ Corresponding author.E-mail address: cappa.stefano@hsr.it (S.F. Cappa).

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028-3932/$ – see front matter © 2007 Elsevier Ltd. All rights reserved.oi:10.1016/j.neuropsychologia.2007.05.012

entences with reduced morphology), and are often impairedn the comprehension of syntactically complex sentences (seerodzinsky, 2000a,b for a review). Sentence comprehension cane impaired also in degenerative brain disorders, and, in partic-lar, in frontotemporal dementia (FTD) (Grossman et al., 1996;esulam, 2001; Miller et al., 1991; Rosen et al., 2002; SnowdenNeary, 1993; Snowden, Neary, Mann, Goulding, & Testa,

992; Thompson, Ballard, Tait, Weintraub, & Mesulam, 1997;eintraub, Rubin, & Mesulam, 1990). Grossman et al. (1996)

eported that, while patients with AD are impaired in single wordomprehension, patients with FTD had sentence comprehension

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ifficulties which could be attributed to impaired processing oframmatical phrase structure. In a subsequent study Grossmant al. (1998) found that grammatical comprehension difficul-ies in FTD correlated with reduced relative cerebral perfusionSPECT) in left frontal and anterior temporal brain regions,hile impaired semantic processing in AD correlated with cere-ral hypoperfusion in inferior parietal and superior temporalegions of the left hemisphere.

The main focus of the studies in FTD has been the evalua-ion of the relationship between working memory and sentenceomprehension. Grammatical and executive components bothontribute to sentence comprehension. The profile of sentenceomprehension difficulties varies across the FTD clinical sub-roups and depends on the sentence processing component thats impaired (Grossman, Rhee, & Moore, 2005b). Sentence pro-essing in FTD patients has been generally assessed with taskselying on the modulation of the syntactic complexity of sen-ences, which is typically associated with an increasing working

emory load (Grossman et al., 2005b).Another way to probe syntactic abilities is by asking the sub-

ects to judge whether sentences are well formed or not. Thispproach allows minimisation of the involvement of workingemory abilities. Typically, the ability to detect morphosyn-

actic anomalies is contrasted with the detection of conceptualor pragmatic) violations. Conceptual and syntactic anomaliesetection have been extensively investigated with event-relatedotentials, which has shed meaningful light on the timing ofhe processes involved in sentence comprehension (Friederici,002). Recently, similar paradigms have been applied to fMRI,howing that grammatical judgements of sentences consistentlynvolve Broca’s region, as well as the superior temporal gyrusilaterally (see Embick, Marantz, Miyashita, O’Neil, & Sakai,000; Grodzinsky & Friederici, 2006 for a recent review). Forxample, Cooke et al. (2006) found an activation of the ven-ral portion of the left inferior frontal cortex while subjectsere asked to judge violations involving three types of syn-

actic features (inflectional morphology, grammatical categorynd transitivity). A more complex pattern emerges in a study ofuperberg et al. (2003), which combined event-related poten-

ials (ERP) and functional magnetic resonance imaging (fMRI).The investigators clearly highlighted that the detection of

onceptual and syntactic anomalies modulated several brainreas to different degrees within a common network of regionsssociated with sentence processing.

The ability to detect syntactic anomalies and how this processelates to disorders of both production and comprehension haseen less thoroughly tackled than sentence comprehension inphasic and demented patients. A classic study by Linebarger,chwartz, and Saffran (1983) found that some patients wereble to detect syntactically ill-formed sentences, despite theirerformance at chance on comprehension tests. They werempaired only on specific structures (tag questions), whichequired high memory resources. In contrast, Wilson and Saygin

2004) reported a generalised impairment of the ability of apha-ic patients to make grammaticality judgments. A recent study,sing an online task not requiring explicit judgment of viola-ions, indicated that in Non-fluent Primary Progressive Aphasia

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gia 45 (2007) 3015–3023

NfPPA), the patients’ defective performance in sentence com-rehension was correlated with slowed processing in an onlineask (Grossman et al., 2005b).

The main aim of this study was to assess the status of syntacticnowledge in FTD and conditions related to it, which are charac-erized by different patterns of pathological brain involvement.he diagnostic label of FTD encompasses a number of hetero-eneous clinical manifestations, in which different patterns ofmpairment involving linguistic processing, executive functionsnd action organization reflect the location of the underlyingathology (Libon et al., 2007). NfPPA and semantic demen-ia (SD) are traditionally the language variants of FTD. NfPPAs characterized by non-fluent aphasia, agrammatism, anomiand phonemic paraphasias associated with a relatively sparedord comprehension (Gorno-Tempini, Dronkers et al., 2004;rossman et al., 1996; Hodges & Patterson, 1996; Neary et al.,998). By contrast, SD is characterized by loss of word meaningnd impaired language comprehension, with preserved syntacticomprehension and production and spared fluency of speech out-ut (Gorno-Tempini, Dronkers et al., 2004; Hodges, Patterson,xbury, & Funnell, 1992).In vivo, regional differences in brain atrophy are associated

ith the clinical features of the FTD variants. Studies in whichoxel-based morphometry (VBM) was performed have shownhat NfPPA is characterized by left inferior frontal and insu-ar atrophy (Gorno-Tempini, Dronkers et al., 2004), while inD the core of the damage is to the anterior temporal lobeGorno-Tempini, Dronkers et al., 2004). The frontal variantf FTD (FvFTD) is characterized by atrophy of the anteriornsula bilaterally, the right middle frontal gyrus, the left ante-ior cingulate gyrus, the left medial superior frontal gyrus andhe left premotor cortex (Rosen et al., 2002). Two other condi-ions, progressive supranuclear palsy (PSP) and the corticobasalegeneration syndrome (CBDS), which overlap both clinicallynd neuropathologically with FTD (for a review, see Kertesz &unoz, 2004), are associated with a relatively specific pattern of

ortical atrophy (McKhann et al., 2001). CBDS is characterizedy an asymmetric (usually left > right) pattern of brain atro-hy that involves the bilateral premotor cortex, superior parietalobes and striatum, while PSP is associated with atrophy of the

idbrain, pons, thalamus and striatum, with minimal involve-ent of the frontal cortex (Boxer et al., 2006; Padovani et al.,

006).In FTD, the pattern of comprehension difficulties appears to

ary depending on the clinical variant at the onset and its evo-ution during the course of the disease (Kertesz, McMonagle,lair, Davidson, & Munoz, 2005). The frontal variant of FTD,hich is characterized by the impairment in executive function-

ng, allows assessment of contribution of executive resourceso sentence processing in FTD. Cooke et al. (2003) in a fMRItudy reported different profiles of activation during sentenceomprehension tasks. In particular, the authors found an acti-ation of both ventral and dorsal portions of inferior frontal

ortex in the left hemisphere in healthy seniors, and under-ined that these activations were associated, respectively, tohe grammatical and working memory components of sentenceomprehension. The same study highlighted that NfPPA patients

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iffered from healthy controls, in that they showed reduced acti-ation of left ventral inferior frontal cortex. Finally, in FvFTDatients there was evidence of a reduced activity of the left dor-al inferior frontal cortex when compared with controls. Theuthors concluded that FTD clinical subgroups have distinctatterns of sentence comprehension deficits, that in part can bescribed to selective interruptions within a large-scale networknderlining sentence processing. SD patients also show a diffi-ulty in sentence processing, which in turn can be attributed toheir lexical-semantic impairment (Hodges & Patterson, 1996;nowden, Goulding, & Neary, 1989).

In the present study we investigated the ability to detectyntactic anomalies, which represent violations of Universalrammar principles, in a relatively large sample of patients

ffected by two subtypes of FTD [SD and FvFTD], and inatients with a clinical diagnosis of PSP or CBDS. The patientsere selected from a larger sample on the basis of their score

above 20/30) on the Mini Mental State Examination (MMSE)Folstein, Folstein, & McHugh, 1975).

Our aim was to assess the ability to detect syntactic andemantic anomalies within these different subgroups of FTDatients, which are characterized by different patterns of cogni-ive and linguistic impairment, reflecting different locations ofhe specific pathological process in the brain.

In particular, we expected to find a more severe impairment inhe detection of syntactic anomalies in the variety associated torefrontal damage (FvFTD) than in SD and in AD patients, whoould be expected to be impaired in the detection of semanticnomalies. In the case of CBDS and PSP, the predictions wereot as clear-cut. Neither condition is typically associated withrominent language impairment, but both diseases affect pre-rontal areas, as well as other cortical and subcortical structuresnvolved in action organization and motor control. It is note-orthy to mention that in the large series recently reported by

osephs et al. (2006) most of the cases clinically classified asfPPA were characterized by PSP and CBDS pathology.

. Participants and methods

.1. Patient and control groups

Patients were recruited from the Department of Neurology at the Universityf Brescia, the San Raffaele Turro Neurology Department, and the Centro Saniovanni di Dio-Fatebenefratelli Scientific Institute of Brescia, Italy.

Thirty-nine patients were diagnosed as affected by FTD according to pub-ished criteria (McKhann et al., 2001; Neary et al., 1998). This group includedour patients with a clinical diagnosis of semantic dementia (SD) and nineatients with FvFTD. In particular, SD patients were characterized by a promi-ent comprehension disorder (impaired understanding of word meaning and/orbject identity) and naming difficulties, while FvFTD patients presented per-onality changes, disorders of social conduct and executive function deficits.ifteen patients were diagnosed as probable PSP according to the criteria sety the National Institute of Neurological Disorders and Stroke (NINDS)-PSPLitvan et al., 1997), and 11 were clinically diagnosed with CBDS (Lang,994). PSP patients showed vertical gaze palsy, repetitive falls, axial rigidity

nd pseudobulbar palsy; CBDS patients had unilateral rigidity and asymmet-ic limb apraxia. In these patients, the extrapyramidal syndrome developedrst and was followed by cognitive changes. An additional inclusion crite-ion was the poor response to l-dopa treatment for both the CBDS and PSProup.

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In order to be included, the patients had been regularly examined for at least.5 years and the initial diagnosis confirmed at follow-up.

Only patients with a mild form of cognitive decline were included (Clinicalementia Rating 0.5–1 and MMSE > 20/30). The reason for this selection is thatreliminary pilot studies indicated that even patients with moderate dementiaad difficulties in understanding the instructions of the task.

In order to assess the impact of mild dementia on the detection of syntacticnomalies, we also included ten patients who had been diagnosed with probablelzheimer disease (AD), based on the criteria from the National Institute ofeurological and Communication Disorders and Stroke Alzheimer disease andelated Disorders Association (NINCDS-ADRDA) (McKhann et al., 2001), asell as ten healthy volunteers, matched for age and education. The latter hadnormal neurological examination and brain MRI, with no history of mental

llness or cognitive decline.All patients underwent a detailed clinical and neurological evaluation. The

otor examination, as well as the levodopa response, was based on the motorxamination section of the Unified Parkinson Disease Rating Scale (UPDRS-II). Upper limb apraxia was evaluated by using a movement imitation test (Deenzi, Motti, & Nichelli, 1980).

Routine laboratory tests including thyroid hormone dosage, vitamin B12,nd serum folate and syphilic serology were available for all patients.

Each patient underwent a structural brain MRI, and visual ratings of MRImages were compatible with the clinical diagnosis. A voxel-based morphometryVBM) analysis was performed in each group and the results have been reportedlsewhere (Borroni et al., 2007; Padovani et al., 2006). Seven out of 11 CBDSatients showed an asymmetric atrophy (left > right).

Patients, with potentially confounding neurological and psychiatric disor-ers, clinically known hearing or vision impairment, with a history of alcoholbuse or psychosis or major depression and MRI evidence of relevant cerebrovas-ular changes were excluded from the study. The use of psychopharmacologicalgents that could interfere with the performance on the test or with the diagnosisas considered as a further exclusion criterion.

Cognitive assessment was followed by an experimental evaluation on a sec-nd visit. Baseline cognitive assessment included screening tests for dementiaMMSE; Clinical Dementia Rating, CDR), and neuropsychological tests for:easoning, language comprehension, verbal fluency, short and long term mem-ry, constructional abilities, apraxia, attention and executive functions (Lezak,owieson, & Loring, 2004). The results of the baseline cognitive assessment are

eported in Table 1. In addition, language functions such as repetition, naming,riting and comprehension were formally assessed with the full Italian versionf the Aachener Aphasie Test (AAT) (Luzzatti et al., 1994).

. Experimental evaluation

.1. Visual and auditory sentence comprehension

For the evaluation of visual and auditory grammatical comprehension wesed the sentence comprehension tasks included in the “Batteria per l’Analisiei Deficit Afasici—BADA” (Miceli, Laudanna, Burani, & Papasso, 1994). Bothasks use simple declarative sentences as stimuli. In the auditory task (n = 60timuli), the sentence was pronounced by the examiner. In the visual task (n = 45)he stimuli were presented on a written card. In both cases, the subject was askedo match the stimulus sentence to one of two pictures. Half of the sentencesere in the active voice, half in the passive one. Active sentences were of the

ubject–verb–object (SVO) form:

l ragazzo abbraccia la ragazzahe boy hugs the girl

Passive sentences were also presented in the canonical word order:ubject–aux-verb-agent:

a ragazza e abbracciata dal ragazzohe girl is hugged by-the boy

In each trial, one of two alternatives represented the correct choice; thether alternative represented a role reversal foil, a morphological foil or a

3018 M. Cotelli et al. / Neuropsychologia 45 (2007) 3015–3023

Table 1Neuropsychological data

SD FvFTD PSP CBDS p

Raven Colored Progressive Matrices 24.9 (6.1) 23.3 (4.8) 24.6 (7.3) 23.5 (10.7) nsStory recall 5.5 (2.8) 8.4 (5.2) 10.3 (3.9) 12.2 (2.9) <0.05Auditory-Verbal Learning Test, immediate recall 23.5 (8.3) 27.5 (6.3) 28.1 (6.6) 30.2 (5.1) nsAuditory-Verbal Learning Test, delayed recall 3.8 (1.7) 5.1 (2.1) 4.7 (2.2) 5.8 (1.9) <0.05Rey-Osterrieth Complex Figure, Copy 27.3 (10.2) 25.2 (9.5) 24.0 (7.7) 25.7 (5.6) nsRey-Osterrieth Complex Figure, Recall 13.0 (4.4) 12.6 (7.2) 12.4 (6.1) 11.6 (5.4) nsDigit Span 5.2 (1.5) 5.1 (1.2) 4.3 (1.5) 4.7 (1.9) nsToken Test 25.6 (2.4) 29.3 (5.2) 28.6 (6.7) 26.8 (5.7) nsFluency, phonemic 18.6 (10.2) 22.5 (11.1) 17.5 (9.4) 27.9 (9.7) <0.05Fluency, semantic 6.5 (2.3) 11.2 (4.2) 29.7 (8.7) 35.0 (6.9) <0.05De Renzi Imitation test 69.1 (4.4) 68.8 (5.6) 67.7 (6.7) 52.7 (4.5) <0.05Trail-Making Test A 90.2 (44.2) 94.5 (39.6) 88.5 (33.4) 73.6 (29.7) nsTrail-Making Test B 166.4 (56.6) 310.2 (147.5) 220.2 (87.9) 140.8 (37.6) <0.05Alertness without auditory warning signal (TEA), ms 339.2 (66.7) 365.5 (73.3) 328.1 (69.7) 338.1 (62.4) nsAlertness with auditory warning signal (TEA), ms 309.5 (82.2) 326.1 (84.3) 299.5 (70.5) 304.7 (69.9) nsDivided Attention (TEA), ms 746.5 (103.5) 1285.5 (96.5) 677.5 (88.5) 681.1 (110.7) <0.05Divided Attention (TEA), omissions 3.0 (1.0) 10.0 (1.0) 6.0 (4.0) 7.0 (3.0) <0.05Wisconsin Card sorting test, Global score 94.6 (12.5) 118.0 (11.2) 100.0 (16.1) 93.4 (23.4) <0.05Wisconsin Card sorting test, Perseverative Responses 48.8 (25.5) 70.5 (16.5) 49.2 (20.2) 33.8 (15.9) <0.05Wisconsin Card sorting test, Non-perseverative Errors 22.3 (6.9) 43.5 (19.5) 15.8 (5.3) 19.2 (5.6) <0.05Wisconsin Card sorting test, Failure to maintain set 2.0 (1.4) 1.0 (1.0) 1.6 (1.4) 2.8 (1.7) nsCognitive estimations, errors 16.6 (3.2) 20.0 (2.0) 14.0 (3.3) 15.8 (2.7) <0.05C

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ognitive estimations, Bizzare Responses 2.5 (1.5)

exical-semantic foil. For trials with a role reversal foil the correct pictureas associated with the representation of the reversal sentence (e.g., for the

entence:

a mucca segue il cavallohe cow follows the horse

he wrong picture depicted a horse following the cow). For trials with morpholog-cal foils, a sentence was presented with the correct target and with an alternativeepresenting either the first or the second noun in a different number (e.g., for theentence:

ragazzi sono abbracciati dalla ragazzahe boys are hugged by-the girl

he wrong picture depicted one boy being hugged by a girl). For trials withexical-semantic foils, a sentence was paired with an alternative that repre-ented a semantically different noun or semantically different action (e.g., forhe sentence:

l cavallo e seguito dal canehe horse is followed by-the dog

he wrong picture depicted a cow followed by a dog). The auditory task included0 sentences in the active voice, 30 in the passive voice (10 active sentences and0 passive sentences for each of the three foil types). The visual task included 23entences in the active voice, 22 in the passive voice (eight active and eight pas-ive sentences for the role reversal foil, eight active and seven passive sentencesor the morphological foil and for the lexical foil). Both tasks were administratedithout time constraints.

.2. Error detection tasks

SD, FvFTD, PSP, CBDS, AD patients and age-matched control subjectsere tested on sentences with morphological or syntactic violations. Both patientroups and controls were also presented with an additional set of sentences withemantic violations.

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The aim of this additional set of sentences was to explore both syntax andemantics, which represent two subsystems of the language system. Moreover,hese sentences allowed us to compare to what extent these two different sub-ystems play a role in an error detection task and to what degree pathologieshat involve them can affect the performance of different subgroups of patientsn this task.

.2.1. Detection of semantic violationsThe ability to detect semantic anomalies was evaluated by means of a seman-

ic coherence task (SC). The stimulus materials consisted of 120 sentences (60orrect and 60 incorrect). In this condition, the sentences were grammaticallyorrect but contained semantic violations, e.g:

’ incendio nel villaggio recita in un attimohe fire in-the village recites in a second

ll sentences were orthographically correct and matched for length and wordrequency. The sentences were adapted from a corpus of sentences used in arevious study (Hahne & Friederici, 2002).

.2.2. Detection of morphological violationsThe ability to detect morphological violations was assessed with

erb–subject agreement (VSAgr). The stimulus materials consist of 120 sen-ences (60 correct and 60 incorrect). The sentences were meaningful but includedisagreement in number, e.g.:

I gatt -i [plur.] am -a [III pers. Sing.] cacciare i topihe cat -s [plural] like -s [singular] to-hunt t the mice

All sentences were orthographically correct and matched for length andord frequency. The sentences were adapted from a corpus of sentences used

n a previous study (Hahne & Friederici, 2002).

.2.3. Detection of syntactic violationsThere were three tasks, assessing different violations of universal grammar:

ronominalization. They involved clitic movement (ClM), interrogatives (WhS)

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nd contrastive focus constructions (CFC). The task consisted in a series of0 sentences presented on test sheets that included well-formed sentences andentences containing syntactic violations. The test was self-paced. Stimuli wereonstructed as follows. Syntactic errors were designed relying on properties ofniversal grammar, i.e. errors that violate universal principles of grammar ratherhan stylistic norms. A prototypical case of violation of universal grammar is theo-called violation of Locality Principles (Chomsky, 1981). Following formalinguistics, by “Locality” we mean the restrictions on the possibility to interpretords that are “far” from the words they immediately refer to. So for example,

n affirmative sentence like John wants to contact the nurse before meeting theoctor could yield two distinct interrogative sentences: who does John want toontact before meeting the doctor versus *who does John want to talk to the nurseefore meeting? The interrogative pronoun who is the complement of contact inhe first sentence and the complement of meet in the second sentence. Despite theact that the two sentences contain exactly the same number of words, only therst sentence is grammatically correct. In the second one, the syntactic relationetween who and the verb it refers to (meet) is said not to be sufficiently “local”r, more specifically, to violate the so called “Subjacency Principle” (Chomsky,981) as signalled by the asterisk. In fact, there were two types of Local-ty principle violations. Along with those involving interrogative sentences,uch as:

quale dottore pensi che Gianni voglia telefonarehich doctor you-think that John wants to-phone

Maria prima di incontrare Pietroo Mary before meeting Peter

ffirmative sentences containing a locality violation have been constructed.n this case, the misplaced element was a clitic (i.e. stressless pronoun) suchs in:

di queste foto, Maria ne pensa che Giannivuole vedere due

f these pictures, Maria of-themclitic thinks that Gianni wantsto-see two

s opposed to:

i queste foto, Maria pensa che Gianni nevuole vedere due

f these pictures, Maria thinks that Gianniof-themclitic wants to-see two

The clitic ne (of them) cannot move too far from the verb it refers to,s in the case of the first sentence. Finally, a third type of error violatingniversal grammar was produced which did not involve locality violations.n this case, the error was related to the so called “contrastive focus inter-retation” where something is negated and contrasted with something elsen the sentence. This operation is sensitive to word order. A simple casean illustrate such a violation. From a given pair of grammatical sentences

ike:

ianni arrivaianni arrives

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able 2emographic and clinical data

SD (n = 4) FvFTD (n = 9) PSP (n = 15)

ge (years) 60.0 (3.6) 65.8 (8.7) 69.9 (8.7)ducation (years) 13.7 (3.3) 7.8 (3.8) 8.2 (4.0)MSE 26.0 (1.2) 25.6 (1.6) 26.5 (2.3)

D: semantic dementia; FvFTD: frontal variant of frontotemporal dementia; PSP: prolzheimer disease and control subjects. MMSE: Mini Mental State Examination. Re

gia 45 (2007) 3015–3023 3019

nd

rriva Giannirrives Gianni

e can only make the following two grammatical combinations:

ianni non arriva ma parteianni not arrives but leaves

Gianni is not arriving: he is leaving” and

on arriva Gianni ma Pietroot arrives Gianni but Peter

It’s not Gianni who arrives: it’s Peter”.The other two options, available on purely combinatorial grounds are

ngrammatical:

Gianni non arriva ma Pietroianni not arrives but Pietro

non arriva Gianni ma parteot arrives Gianni but leaves

Summarizing, there were three types of errors: locality errors with interrog-tives, locality errors with affirmatives (clitic constructions) and errors withocus interpretation. The subject was asked to decide if the sentence wasorrect on the basis of the syntactic form. Each of the three syntactic typespronominalization involving clitic movement, interrogatives and contrastiveocus constructions) occurred 20 times (10 correct sentences and 10 incorrectentences).

.3. Procedure

The material was presented visually and patients were required to judgehether the sentences were correct or incorrect. Sentences were matched for

ength and complexity in different conditions. The tasks did not involve anyime constraints.

Sentence comprehension evaluation was administered by an experiencedxaminer in a quiet room in the hospital. Statistical analysis was performed withTATISTICA software.

. Results

.1. Clinical and demographic characteristics

Demographic and clinical data of patients and control partic-

pants are reported in Table 2.

One-way ANOVA performed on age showed a significantain effect of Group (F(5, 53) = 3.3, p < 0.05). A Bonferroni

ost hoc analysis revealed that AD patients were significantly

CBDS (n = 11) AD (n = 10) Control subjects (n = 10)

64.6 (5.5) 79.4 (7.2) 68.1 (12.4)6.0 (2.4) 8.1 (4.3) 7.4 (1.5)

25.2 (2.2) 22.4 (1.7) 29.2 (0.7)

gressive supranuclear palsy; CBDS: corticobasal degeneration syndrome; AD:sults are expressed as means; standard deviations between brackets.

3 chologia 45 (2007) 3015–3023

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020 M. Cotelli et al. / Neuropsy

lder (79.4 ± 2.4 years) than FvFTD patients (65.8 ± 8.7 years;< 0.05) and CBDS patients (64.6 ± 5.5 years; p < 0.01). One-ay ANOVA performed on education showed a significant main

ffect of Group (F(5, 53) = 2.8, p < 0.05). A Bonferroni postoc analysis revealed that only SD patients had higher edu-ation (13.7 ± 3.3 years) than CBDS patients (6.0 ± 2.4 years;< 0.01).

One-way ANOVA performed on MMSE score showed a sig-ificant main effect of Group (F(5, 53) = 12.7, p < 0.001). Aonferroni post hoc analysis revealed that AD patients had

ignificantly lower MMSE score (22.4 ± 1.7) than SD patients26.0 ± 1.2; p < 0.05), FvFTD patients (25.6 ± 1.6; p < 0.05),SP patients (26.5 ± 2.3; p < 0.001), CBDS patients (25.2 ± 2.2;< 0.05) and control subjects (29.2 ± 0.7; p < 0.001). More-ver, control subjects differed significantly from FvFTD patientsp < 0.01), PSP patients (p < 0.05), CBDS patients (p < 0.001)nd AD patients (p < 0.001).

.2. Neuropsychological assessment

We performed one-way ANOVAs on the neuropsychologicalest scores, with the patient subgroup as a between-subject fac-or, and subsequent post hoc mean comparisons corrected for

ultiple comparisons.SD patients showed significant lower performances for Story

ecall and Auditory-Verbal Learning Test compared to all otherroups (p < 0.05). In addition SD patients obtained a low scoren Verbal Fluency Tests (p < 0.05). FvFTD patients performedorse on executive measures such as TMT B, Divided Attention

ask, Wisconsin Card Sorting Test and Cognitive Estimation Testp < 0.05) Finally, CBDS patients had inferior performance onpper limb apraxia, evaluated with a movement imitation testDe Renzi et al., 1980) (p < 0.05).

.3. Linguistic profile of SD, FvFTD, PSP and CBDS,ccording to the Aachener Aphasie Test

Language information about SD, FvFTD, PSP and CBDSatients is summarized in Table 3, along with the patients’ercentage of correct responses on the four tasks (repetition,

aming, writing and comprehension) of the Italian version ofhe Aachener Aphasie Test. One-way ANOVAs failed to indi-ate significant differences between groups in repetition, writingnd comprehension subtests. A significant difference between

able 3achener Aphasia Test performances in FTD

SD FvFTD PSP CBDS

epetition(N = 150)

97.8 (1.7) 96.2 (4.3) 96.6 (2.9) 94.4 (3.9)

riting (N = 90) 91.7 (13.1) 93.6 (6.4) 95.3 (8.8) 83.0 (12.7)aming (N = 120) 72.3 (17.1) 92.0 (5.5) 92.7 (6.4) 88.9 (10.8)omprehension(N = 120)

84.5 (11.1) 84.1 (11.0) 80.2 (11.6) 88.9 (10.1)

D: semantic dementia; FvFTD: frontal variant of frontotemporal dementia;SP: progressive supranuclear palsy; CBDS: corticobasal degeneration syn-rome. Percentage of correct responses and standard deviations are reported.

t

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4

H

BADA). SD: semantic dementia; FvFTD: frontal variant of frontotemporalementia; PSP: progressive supranuclear palsy; CBDS: corticobasal degener-tion syndrome; AD: Alzheimer disease; C: control subjects. *p < 0.05.

roups was present for the naming subtest (F(3, 31) = 4.6,< 0.01).

A Bonferroni post hoc analysis evidenced that SD patientsere significantly more impaired in naming than other groups

SD versus CBDS: p = 0.05; SD versus FvFTD: p < 0.05; SDersus PSP: p < 0.01).

.4. Sentence comprehension results by BADA

We performed a one-way ANOVA on the raw percentage oforrect responses. This analysis for comprehension and GroupSD, FvFTD, PSP, CBDS, AD, control subjects) indicated aignificant main effect of Group (F(5, 47) = 2.6, p < 0.05). OnlyD patients were significantly impaired in the comprehension

ask compared to control subjects (p < 0.05). Mean scores areummarized in Fig. 1.

.5. Error detection tasks

We first attempted to use the d′-statistics, derived from theignal detection theory, but in order to avoid ± infinite values wedopted here the traditional “correct response” and “hits-falselarms” rates.

The results on the experimental tests were analysed withruskal–Wallis ANOVA to assess the effects of group on both

he percentage of correct responses and Hits-False alarms.

.5.1. Correct responses analysisThe analyses underlined a main effect of Group in four of

he five kinds of sentence violations: SC (H = 12.1, p < 0.05),SAgr (H = 17.7, p < 0.01), ClM (H = 20.5, p < 0.001) and WhS

H = 21.3, p < 0.001). Multiple comparisons highlighted thatn the FTD group only patients with CBDS were signifi-antly impaired in VSAgr (p < 0.01), ClM (p < 0.001) and WhSp < 0.001) when compared to normal controls. In addition, ADatients did not perform as well in SC (p < 0.05) and in WhSp < 0.01) compared to control subjects. The significant resultsre shown in Fig. 2.

.5.2. Hits-False alarms analysisNo difference was found between the correct responses and

its-False alarm analysis. Also the last analysis showed a main

M. Cotelli et al. / Neuropsychologia 45 (2007) 3015–3023 3021

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ig. 2. Percentage of correct responses in tests of Semantic Coherence (SC) (Pannvolving Clitic Movement (ClM) task (Panel C) and Interrogatives (WhS) (PaSP: progressive supranuclear palsy; CBDS: corticobasal degeneration syndrom

ffect of Group for four of the five kinds of sentence viola-ions: SC (H = 12.0, p < 0.05), VSAgr (H = 16.7, p < 0.01), ClMH = 19.9, p < 0.01) and WhS (H = 21.1, p < 0.001). Multipleomparisons showed again that only patients with CBDS wereignificantly impaired in VSAgr (p < 0.01), ClM (p < 0.001) and

hS (p < 0.001) compared to normal controls. In addition, ADatients were impaired in SC (p < 0.05) and WhS (p < 0.01)ompared to control subjects.

To sum up, only CBDS showed evidence of a selective impair-ent in the detection of syntactic violations.

. Discussion

The main outcome of this study is that only the CBDSubgroup of patients shows a specific impairment of syntac-ic knowledge, as reflected by a defective detection of syntacticnomalies. The effect was found in patients who had no clini-al evidence of aphasia, and was not associated with a defectiveerformance in grammatical comprehension tests. In addition,his impairment cannot be attributed to impaired working mem-ry, since the experimental sentences were presented visually,n a self-paced way. Moreover, as shown in Table 1, the FvFTDubgroup included in our study was significantly more impairedhan other subgroups in executive tasks, such as the Trail Mak-ng Test, the Wisconsin Card Sorting Test, the Divided Attentionnd the Cognitive estimation, as well as the detection task.

The fact that CBDS patients were impaired in the detectionf syntactic anomalies, but not in the sentence comprehensionask is remindful of the dissociation between performance inentence comprehension and in grammatical judgment tasks

bsCp

Verb–Subject Agreement (VSAgr) detection task (Panel B), Pronominalization. SD: semantic dementia; FvFTD: frontal variant of frontotemporal dementia;

D: Alzheimer disease; C: control subjects. *p < 0.05.

eported by (Linebarger et al., 1983) in agrammatic aphasicatients. In the latter case, the patients showed a preserved per-ormance in judging the well-formedness of sentences, but werempaired in sentence comprehension. This finding was attributedo a defective usage of the correct results of syntactic analysis toetermine sentence meaning. The reverse dissociation reportedere is compatible with the idea that the defective syntacticnowledge shown by CBDS patients could be effectively com-ensated by residual syntactic resources, as well as by lexicalemantic and pragmatic cues. An integration between syntac-ic and semantic information during sentence comprehension isllowed by both interactionist and serial psycholinguistic mod-ls (Friederici, 2002). However, further studies are needed on theossible impact of selective aspects of syntactic impairment onhe understanding of specific sentence types, as in the case, forxample, of the trace-deletion hypothesis (Grodzinsky, 1986;rodzinsky, 2000a,b; Grodzinsky & Finkel, 1998; Mauner,romkin, & Cornell, 1993).

There is increasing evidence that language disorders cane prominent in CBDS patients (Bak, Crawford, Hearn,athuranath, & Hodges, 2005; Cotelli et al., 2006; Gibb,

uthert, & Marsden, 1989; Graham, Bak, Patterson, & Hodges,003; Lippa, Smith, & Fontneau, 1990; Mathuranath, Xuereb,ak, & Hodges, 2000; Mimura et al., 2001; Rebeiz, Kolodny, &ichardson, 1968). Furthermore, many patients with a clinicaliagnosis of NfPPA or speech apraxia turn out to be affected

y CBDS neuropathology (Josephs et al., 2006). Thus, whileyntactic abilities have not been systematically examined inBDS patients, the present findings may be extended to NfPPAatients, who were not included in our study. There is neu-

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oimaging evidence that the detection of syntactic anomaliesngages the activation of Broca’s area and superior temporalyrus (Embick et al., 2000; Grodzinsky & Friederici, 2006).herefore the activity of these areas may be crucially com-romised in patients diagnosed with CBDS (Gorno-Tempini,urray, Rankin, Weiner, & Miller, 2004).In contrast, SD, PSP and FvFTD patients did not show

vidence of defective sentence comprehension or detection ofnomalies. In the case of SD, this was not unexpected as theyntactic abilities in these patients are considered to be sparedHodges & Patterson, 1996). In the case of PSP, there is now evi-ence that performance of these patients can be associated withclinical picture of non-fluent aphasia (Josephs et al., 2006)

ven though recent studies have emphasized the presence of adynamic aphasia”, a clinical framework characterized by gen-ral “generation” impairment, which may be compatible withreserved syntactic knowledge (Robinson, Shallice, & Cipolotti,006).

On the other hand, our prediction of a defective performancey FvFTD patient was not confirmed by the present data. Theifference with previous reports about defective sentence com-rehension in FTD (Cooke et al., 2003; Grossman et al., 1996;rossman & Moore, 2005) may be attributed to the fact that we

elected our patients in an early stage of the disease and theyll presented mild cognitive deterioration. We adhered to theseriteria when selecting the patients in order to make sure thathey could understand the relatively complex task instructions.

In a recent study, Grossman et al. (2005a) examined theypothesis that both grammatical and resource factors contributeo impaired sentence comprehension in FTD. The authors foundhat, while Progressive Non-Fluent Aphasia (PNFA) patientsre significantly impaired in off-line sentence comprehension,vFTD show modest difficulties in this task this result corre-

ated with working memory, planning and inhibitory controlerformances. In FTD the selective anatomic distribution of theeurodegenerative process may result in a dissociation betweenhe ventral portions of left inferior frontal cortex, responsibleor grammatical processing, and the dorsal region, which playscentral role in verbal working memory (Cooke et al., 2003).preservation of the ventral portions of left inferior frontal

ortex in the early stages of FvFTD may explain their normalerformance in sentence comprehension in the absence of a highorking memory load.Another unexpected finding is that the SD patients were not

mpaired in detecting semantic violations. A prominent disor-er of semantic knowledge is the clinical hallmark of semanticementia, and has been attributed to a degradation of amodalemantic representations, typically tested with single word andicture processing tasks (Jefferies, Frankish, & Lambon Ralph,003). The violations used in this experiment involved wordeaning, rather than world knowledge, i.e. the sentences did not

llow any meaningful integration between noun and verb (for aiscussion of this distinction, see Hagoort, Hald, Bastiaansen,

Petersson, 2004). It is noteworthy that, while SD patients per-

ormed within normal range in the semantic violation detectionask, AD patients, who in the early stages are usually unimpairedn single word comprehension, showed a defective performance

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n this task. We plan to pursue this issue in more detail in futurenvestigations.

cknowledgements

We wish to thank the patients and their caregivers for theiratience.

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