Universal grammar in the frontotemporal dementia spectrum

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Neuropsychologia 45 (2007) 3015–3023

Universal grammar in the frontotemporal dementia spectrum Evidence 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, Italy Department of Neurology, University of Brescia, Brescia, Italy c Vita Salute University and San Raffaele Scientific Institute, DIBIT Via Olgettina 58, 20132 Milano, Italy d Department of General Psychology, University of Padua, Padua, Italy b

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

Abstract Introduction: While sentence comprehension has been reported to be defective in frontotemporal dementia (FTD), it is still unclear if this disorder reflects the presence of syntactic impairment, or may be attributed to other factors, such as executive or working memory dysfunction. In order to assess the status of syntactic knowledge in a group of patients belonging to the FTD spectrum, we investigated their ability to detect violations of Universal Grammar principles in a sentence judgement task. Methods: The group included four semantic dementia patients (SD), nine frontal variant of FTD patients (FvFTD), 15 progressive supranuclear palsy (PSP) patients, and 11 corticobasal degeneration syndrome (CBDS) patients. Their performance was compared to a group of 10 patients with mild probable Alzheimer disease (AD) and to 10 healthy volunteers. The patients underwent a standard aphasia test and a sentence comprehension test. The experimental study included five kinds of violations: semantic coherence (SC), verb–subject agreement (VSAgr), pronominalization involving clitic movement (ClM), interrogatives (WhS) and contrastive focus constructions (CFC). Results: The FTD patients performed within normal range in the aphasia test, and in the sentence comprehension test. Within the FTD subgroups, only patients with CBDS were significantly impaired in detecting three of the five kinds of violations. AD patients were also impaired in the detection of WhS and SC anomalies and in sentence comprehension. Discussion: The present findings indicate that, within the FTD spectrum, an impairment of syntactic knowledge can be found only in CBDS patients, even in the absence of clinical evidence of aphasia. © 2007 Elsevier Ltd. All rights reserved. Keywords: FTD; Syntax; Comprehension; CBDS; PSP; Language impairment

1. Introduction The ability to produce and understand sentences requires the computation of syntactic structures, and is frequently affected by neurological damage. Typically, patients with focal brain damage involving Broca’s area show agrammatism in production (i.e. they tend to produce short, syntactically simplified

Corresponding author. E-mail address: [email protected] (S.F. Cappa).

0028-3932/$ – see front matter © 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropsychologia.2007.05.012

sentences with reduced morphology), and are often impaired in the comprehension of syntactically complex sentences (see Grodzinsky, 2000a,b for a review). Sentence comprehension can be impaired also in degenerative brain disorders, and, in particular, in frontotemporal dementia (FTD) (Grossman et al., 1996; Mesulam, 2001; Miller et al., 1991; Rosen et al., 2002; Snowden & Neary, 1993; Snowden, Neary, Mann, Goulding, & Testa, 1992; Thompson, Ballard, Tait, Weintraub, & Mesulam, 1997; Weintraub, Rubin, & Mesulam, 1990). Grossman et al. (1996) reported that, while patients with AD are impaired in single word comprehension, patients with FTD had sentence comprehension


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

difficulties which could be attributed to impaired processing of grammatical phrase structure. In a subsequent study Grossman et al. (1998) found that grammatical comprehension difficulties in FTD correlated with reduced relative cerebral perfusion (SPECT) in left frontal and anterior temporal brain regions, while impaired semantic processing in AD correlated with cerebral hypoperfusion in inferior parietal and superior temporal regions of the left hemisphere. The main focus of the studies in FTD has been the evaluation of the relationship between working memory and sentence comprehension. Grammatical and executive components both contribute to sentence comprehension. The profile of sentence comprehension difficulties varies across the FTD clinical subgroups and depends on the sentence processing component that is impaired (Grossman, Rhee, & Moore, 2005b). Sentence processing in FTD patients has been generally assessed with tasks relying on the modulation of the syntactic complexity of sentences, which is typically associated with an increasing working memory load (Grossman et al., 2005b). Another way to probe syntactic abilities is by asking the subjects to judge whether sentences are well formed or not. This approach allows minimisation of the involvement of working memory abilities. Typically, the ability to detect morphosyntactic anomalies is contrasted with the detection of conceptual (or pragmatic) violations. Conceptual and syntactic anomalies detection have been extensively investigated with event-related potentials, which has shed meaningful light on the timing of the processes involved in sentence comprehension (Friederici, 2002). Recently, similar paradigms have been applied to fMRI, showing that grammatical judgements of sentences consistently involve Broca’s region, as well as the superior temporal gyrus bilaterally (see Embick, Marantz, Miyashita, O’Neil, & Sakai, 2000; Grodzinsky & Friederici, 2006 for a recent review). For example, Cooke et al. (2006) found an activation of the ventral portion of the left inferior frontal cortex while subjects were asked to judge violations involving three types of syntactic features (inflectional morphology, grammatical category and transitivity). A more complex pattern emerges in a study of Kuperberg et al. (2003), which combined event-related potentials (ERP) and functional magnetic resonance imaging (fMRI). The investigators clearly highlighted that the detection of conceptual and syntactic anomalies modulated several brain areas to different degrees within a common network of regions associated with sentence processing. The ability to detect syntactic anomalies and how this process relates to disorders of both production and comprehension has been less thoroughly tackled than sentence comprehension in aphasic and demented patients. A classic study by Linebarger, Schwartz, and Saffran (1983) found that some patients were able to detect syntactically ill-formed sentences, despite their performance at chance on comprehension tests. They were impaired only on specific structures (tag questions), which required high memory resources. In contrast, Wilson and Saygin (2004) reported a generalised impairment of the ability of aphasic patients to make grammaticality judgments. A recent study, using an online task not requiring explicit judgment of violations, indicated that in Non-fluent Primary Progressive Aphasia

(NfPPA), the patients’ defective performance in sentence comprehension was correlated with slowed processing in an online task (Grossman et al., 2005b). The main aim of this study was to assess the status of syntactic knowledge in FTD and conditions related to it, which are characterized by different patterns of pathological brain involvement. The diagnostic label of FTD encompasses a number of heterogeneous clinical manifestations, in which different patterns of impairment involving linguistic processing, executive functions and action organization reflect the location of the underlying pathology (Libon et al., 2007). NfPPA and semantic dementia (SD) are traditionally the language variants of FTD. NfPPA is characterized by non-fluent aphasia, agrammatism, anomia and phonemic paraphasias associated with a relatively spared word comprehension (Gorno-Tempini, Dronkers et al., 2004; Grossman et al., 1996; Hodges & Patterson, 1996; Neary et al., 1998). By contrast, SD is characterized by loss of word meaning and impaired language comprehension, with preserved syntactic comprehension and production and spared fluency of speech output (Gorno-Tempini, Dronkers et al., 2004; Hodges, Patterson, Oxbury, & Funnell, 1992). In vivo, regional differences in brain atrophy are associated with the clinical features of the FTD variants. Studies in which voxel-based morphometry (VBM) was performed have shown that NfPPA is characterized by left inferior frontal and insular atrophy (Gorno-Tempini, Dronkers et al., 2004), while in SD the core of the damage is to the anterior temporal lobe (Gorno-Tempini, Dronkers et al., 2004). The frontal variant of FTD (FvFTD) is characterized by atrophy of the anterior insula bilaterally, the right middle frontal gyrus, the left anterior cingulate gyrus, the left medial superior frontal gyrus and the left premotor cortex (Rosen et al., 2002). Two other conditions, progressive supranuclear palsy (PSP) and the corticobasal degeneration syndrome (CBDS), which overlap both clinically and neuropathologically with FTD (for a review, see Kertesz & Munoz, 2004), are associated with a relatively specific pattern of cortical atrophy (McKhann et al., 2001). CBDS is characterized by an asymmetric (usually left > right) pattern of brain atrophy that involves the bilateral premotor cortex, superior parietal lobes and striatum, while PSP is associated with atrophy of the midbrain, pons, thalamus and striatum, with minimal involvement of the frontal cortex (Boxer et al., 2006; Padovani et al., 2006). In FTD, the pattern of comprehension difficulties appears to vary depending on the clinical variant at the onset and its evolution during the course of the disease (Kertesz, McMonagle, Blair, Davidson, & Munoz, 2005). The frontal variant of FTD, which is characterized by the impairment in executive functioning, allows assessment of contribution of executive resources to sentence processing in FTD. Cooke et al. (2003) in a fMRI study reported different profiles of activation during sentence comprehension tasks. In particular, the authors found an activation of both ventral and dorsal portions of inferior frontal cortex in the left hemisphere in healthy seniors, and underlined that these activations were associated, respectively, to the grammatical and working memory components of sentence comprehension. The same study highlighted that NfPPA patients

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

differed from healthy controls, in that they showed reduced activation of left ventral inferior frontal cortex. Finally, in FvFTD patients there was evidence of a reduced activity of the left dorsal inferior frontal cortex when compared with controls. The authors concluded that FTD clinical subgroups have distinct patterns of sentence comprehension deficits, that in part can be ascribed to selective interruptions within a large-scale network underlining sentence processing. SD patients also show a difficulty in sentence processing, which in turn can be attributed to their lexical-semantic impairment (Hodges & Patterson, 1996; Snowden, Goulding, & Neary, 1989). In the present study we investigated the ability to detect syntactic anomalies, which represent violations of Universal Grammar principles, in a relatively large sample of patients affected by two subtypes of FTD [SD and FvFTD], and in patients with a clinical diagnosis of PSP or CBDS. The patients were 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 and semantic anomalies within these different subgroups of FTD patients, which are characterized by different patterns of cognitive and linguistic impairment, reflecting different locations of the specific pathological process in the brain. In particular, we expected to find a more severe impairment in the detection of syntactic anomalies in the variety associated to prefrontal damage (FvFTD) than in SD and in AD patients, who could be expected to be impaired in the detection of semantic anomalies. In the case of CBDS and PSP, the predictions were not as clear-cut. Neither condition is typically associated with prominent language impairment, but both diseases affect prefrontal areas, as well as other cortical and subcortical structures involved in action organization and motor control. It is noteworthy to mention that in the large series recently reported by Josephs et al. (2006) most of the cases clinically classified as NfPPA were characterized by PSP and CBDS pathology.


In order to be included, the patients had been regularly examined for at least 1.5 years and the initial diagnosis confirmed at follow-up. Only patients with a mild form of cognitive decline were included (Clinical Dementia Rating 0.5–1 and MMSE > 20/30). The reason for this selection is that preliminary pilot studies indicated that even patients with moderate dementia had difficulties in understanding the instructions of the task. In order to assess the impact of mild dementia on the detection of syntactic anomalies, we also included ten patients who had been diagnosed with probable Alzheimer disease (AD), based on the criteria from the National Institute of Neurological and Communication Disorders and Stroke Alzheimer disease and Related Disorders Association (NINCDS-ADRDA) (McKhann et al., 2001), as well as ten healthy volunteers, matched for age and education. The latter had a normal neurological examination and brain MRI, with no history of mental illness or cognitive decline. All patients underwent a detailed clinical and neurological evaluation. The motor examination, as well as the levodopa response, was based on the motor examination section of the Unified Parkinson Disease Rating Scale (UPDRSIII). Upper limb apraxia was evaluated by using a movement imitation test (De Renzi, Motti, & Nichelli, 1980). Routine laboratory tests including thyroid hormone dosage, vitamin B12, and serum folate and syphilic serology were available for all patients. Each patient underwent a structural brain MRI, and visual ratings of MRI images were compatible with the clinical diagnosis. A voxel-based morphometry (VBM) analysis was performed in each group and the results have been reported elsewhere (Borroni et al., 2007; Padovani et al., 2006). Seven out of 11 CBDS patients showed an asymmetric atrophy (left > right). Patients, with potentially confounding neurological and psychiatric disorders, clinically known hearing or vision impairment, with a history of alcohol abuse or psychosis or major depression and MRI evidence of relevant cerebrovascular changes were excluded from the study. The use of psychopharmacological agents that could interfere with the performance on the test or with the diagnosis was considered as a further exclusion criterion. Cognitive assessment was followed by an experimental evaluation on a second visit. Baseline cognitive assessment included screening tests for dementia (MMSE; Clinical Dementia Rating, CDR), and neuropsychological tests for: reasoning, language comprehension, verbal fluency, short and long term memory, constructional abilities, apraxia, attention and executive functions (Lezak, Howieson, & Loring, 2004). The results of the baseline cognitive assessment are reported in Table 1. In addition, language functions such as repetition, naming, writing and comprehension were formally assessed with the full Italian version of the Aachener Aphasie Test (AAT) (Luzzatti et al., 1994).

3. Experimental evaluation

2. Participants and methods

3.1. Visual and auditory sentence comprehension

2.1. Patient and control groups

For the evaluation of visual and auditory grammatical comprehension we used the sentence comprehension tasks included in the “Batteria per l’Analisi dei Deficit Afasici—BADA” (Miceli, Laudanna, Burani, & Papasso, 1994). Both tasks use simple declarative sentences as stimuli. In the auditory task (n = 60 stimuli), the sentence was pronounced by the examiner. In the visual task (n = 45) the stimuli were presented on a written card. In both cases, the subject was asked to match the stimulus sentence to one of two pictures. Half of the sentences were in the active voice, half in the passive one. Active sentences were of the subject–verb–object (SVO) form:

Patients were recruited from the Department of Neurology at the University of Brescia, the San Raffaele Turro Neurology Department, and the Centro San Giovanni di Dio-Fatebenefratelli Scientific Institute of Brescia, Italy. Thirty-nine patients were diagnosed as affected by FTD according to published criteria (McKhann et al., 2001; Neary et al., 1998). This group included four patients with a clinical diagnosis of semantic dementia (SD) and nine patients with FvFTD. In particular, SD patients were characterized by a prominent comprehension disorder (impaired understanding of word meaning and/or object identity) and naming difficulties, while FvFTD patients presented personality changes, disorders of social conduct and executive function deficits. Fifteen patients were diagnosed as probable PSP according to the criteria set by the National Institute of Neurological Disorders and Stroke (NINDS)-PSP (Litvan et al., 1997), and 11 were clinically diagnosed with CBDS (Lang, 1994). PSP patients showed vertical gaze palsy, repetitive falls, axial rigidity and pseudobulbar palsy; CBDS patients had unilateral rigidity and asymmetric limb apraxia. In these patients, the extrapyramidal syndrome developed first and was followed by cognitive changes. An additional inclusion criterion was the poor response to l-dopa treatment for both the CBDS and PSP group.

il the

ragazzo boy

abbraccia hugs

la the

ragazza girl

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

ragazza girl

e` is

abbracciata hugged

dal ragazzo by-the boy

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


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

Table 1 Neuropsychological data

Raven Colored Progressive Matrices Story recall Auditory-Verbal Learning Test, immediate recall Auditory-Verbal Learning Test, delayed recall Rey-Osterrieth Complex Figure, Copy Rey-Osterrieth Complex Figure, Recall Digit Span Token Test Fluency, phonemic Fluency, semantic De Renzi Imitation test Trail-Making Test A Trail-Making Test B Alertness without auditory warning signal (TEA), ms Alertness with auditory warning signal (TEA), ms Divided Attention (TEA), ms Divided Attention (TEA), omissions Wisconsin Card sorting test, Global score Wisconsin Card sorting test, Perseverative Responses Wisconsin Card sorting test, Non-perseverative Errors Wisconsin Card sorting test, Failure to maintain set Cognitive estimations, errors Cognitive estimations, Bizzare Responses






24.9 (6.1) 5.5 (2.8) 23.5 (8.3) 3.8 (1.7) 27.3 (10.2) 13.0 (4.4) 5.2 (1.5) 25.6 (2.4) 18.6 (10.2) 6.5 (2.3) 69.1 (4.4) 90.2 (44.2) 166.4 (56.6) 339.2 (66.7) 309.5 (82.2) 746.5 (103.5) 3.0 (1.0) 94.6 (12.5) 48.8 (25.5) 22.3 (6.9) 2.0 (1.4) 16.6 (3.2) 2.5 (1.5)

23.3 (4.8) 8.4 (5.2) 27.5 (6.3) 5.1 (2.1) 25.2 (9.5) 12.6 (7.2) 5.1 (1.2) 29.3 (5.2) 22.5 (11.1) 11.2 (4.2) 68.8 (5.6) 94.5 (39.6) 310.2 (147.5) 365.5 (73.3) 326.1 (84.3) 1285.5 (96.5) 10.0 (1.0) 118.0 (11.2) 70.5 (16.5) 43.5 (19.5) 1.0 (1.0) 20.0 (2.0) 7.5 (3.5)

24.6 (7.3) 10.3 (3.9) 28.1 (6.6) 4.7 (2.2) 24.0 (7.7) 12.4 (6.1) 4.3 (1.5) 28.6 (6.7) 17.5 (9.4) 29.7 (8.7) 67.7 (6.7) 88.5 (33.4) 220.2 (87.9) 328.1 (69.7) 299.5 (70.5) 677.5 (88.5) 6.0 (4.0) 100.0 (16.1) 49.2 (20.2) 15.8 (5.3) 1.6 (1.4) 14.0 (3.3) 2.0 (2.3)

23.5 (10.7) 12.2 (2.9) 30.2 (5.1) 5.8 (1.9) 25.7 (5.6) 11.6 (5.4) 4.7 (1.9) 26.8 (5.7) 27.9 (9.7) 35.0 (6.9) 52.7 (4.5) 73.6 (29.7) 140.8 (37.6) 338.1 (62.4) 304.7 (69.9) 681.1 (110.7) 7.0 (3.0) 93.4 (23.4) 33.8 (15.9) 19.2 (5.6) 2.8 (1.7) 15.8 (2.7) 3.1 (1.3)

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