Brain & Language 135 (2014) 57–65

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Primary progressive aphasia: Linguistic patterns and clinical variants Maria Caterina Silveri a,⇑, Emanuele Pravatà b,1, Anna Clelia Brita a, Erika Improta a, Nicoletta Ciccarelli a, Paola Rossi a, Cesare Colosimo b a b

Medicine of the Ageing, Department of Geriatrics, Neuroscience and Orthopedics, Italy Department of Neuroimaging, Catholic University, Roma, Italy

a r t i c l e

i n f o

Article history: Accepted 15 May 2014

Keywords: Primary progressive aphasia Apraxia of speech Semantic deficit Phonological deficit Agrammatism Semantic dementia Alzheimer’s disease Corticobasal degeneration

a b s t r a c t We investigated whether primary progressive aphasias (PPA) reflect non-random degradation of linguistic dimensions that might be supported by different neural subsystems and to what extent this degradation contributes to the emergence of clinical entities: semantic (S), logopenic (L) and nonfluent (NF) aphasia; apraxia of speech was also considered if associated with language disorders (AOS/aph). Fortytwo aphasic patients are reported. Two main definable patterns of linguistic deficits tended to emerge that corresponded with identifiable patterns of brain atrophy, and probably diseases: the S variant, which principally expresses the impact of a ‘‘deep’’ cognitive (semantic) disorder on language, and AOS/aph in which ‘‘peripheral’’ executive components play a significant role. By contrast, NF aphasia emerged as a heterogeneous variant due to disorganization of various dimensions within the linguistic domain, that assumes different patterns depending on the differential distribution of atrophy in the perisylvian regions. Ó 2014 Elsevier Inc. All rights reserved.

1. Introduction Since Mesulam’s (1982, 2001) seminal observations, an increasing number of studies have suggested the existence of distinguishable clinical forms of primary language disorders. Classification of the primary progressive aphasias (PPA) into clinical variants (Gorno-Tempini et al., 2011) is primarily based on the characteristics of speech production and single-word and sentence processing. By using high-resolution MRI with grouplevel, voxel-wise statistical analyses of grey matter volumes and cortical thickness (Gorno-Tempini et al., 2004; Grossman, 2010; Mesulam, Wieneke, Thompson, Rogalski, & Weintraub, 2009; Wilson et al., 2009), previous studies were able to correlate three different syndromic variants of PPA (semantic – S, logopenic – L and nonfluent – NF) with distinct patterns of regional cortical atrophy. Atrophic changes in the anterior and lateral temporal lobe were correlated with the S variant, in the anterior perisylvian regions with the NF variant and in the posterior perisylvian regions with the L variant (Grossman, 2010). These atrophic patterns

⇑ Corresponding author. Address: Catholic University, Centre for Cognitive Disorders and Alzheimer’s Disease, Department of Geriatrics, Neurosciences and Orthopedics, Largo A. Gemelli, 8, 00168 Rome, Italy. Fax: +39 063051911. E-mail address: [email protected] (M.C. Silveri). 1 Present address: Neurocenter of Southern Switzerland, Department of Neuroradiology, Via Tesserete 46 – 6900, Lugano, Switzerland. http://dx.doi.org/10.1016/j.bandl.2014.05.004 0093-934X/Ó 2014 Elsevier Inc. All rights reserved.

were found to be lateralized in the left hemisphere (Mesulam et al., 2009). But, thanks to the fine-grained descriptions of the patterns of language disorders that emerge when explored using the sophisticated tools of cognitive neuropsychology, it is clear that the boundaries between the various subtypes of aphasia blend into each other and a virtually unlimited number of intermediate forms can be observed. Thus, although the classification of language disorders into main syndromes has clinical value, from a theoretical point of view the question of aphasia classification is still open. In fact, two issues are still being discussed in this regard: the basis on which combinations of symptoms supposed to represent the core feature of an aphasic syndrome should be predicted (Kohn & Smith, 1992) and whether patients’ symptoms are sufficiently homogeneous to allow separating them into welldefined types of aphasia (Schwartz & Dell, 2010). Confirmation that degeneration in the left perisylvian regions gives rise to definable patterns of linguistic disorders would support the hypothesis that the emergence of different types of aphasia reflects the functional organization of language in the brain and not an assembly of symptoms generated by a random distribution of neural damage. In fact, patterns of symptoms might reflect involution of specific neural networks that have specific functions in language organization. In this perspective, PPA could provide information complementary to that provided by the vascular forms of aphasia to define the neural networks exposed to

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selective neurodegenerative changes that can lead to distinct language impairments. Pathological and genetic markers have sometimes been reported in association with defined patterns of neurodegeneration correlated with different diseases and language disorders (Caso et al., 2012; Rohrer, Rossor, & Warren, 2010). This supports the hypothesis that different aphasia variants-phenotypes might represent stable patterns of symptoms subtended by specific underlying diseases with predictable histopathological and genetic patterns (Grossman, 2010). This multimodal approach to aphasia is promising; thus far, however, consistent correspondence between aphasia variants and specific pathological entities has not been found (Drachman, 2011). However, aphasia is not just a clinical entity. From a psycholinguistic point of view it reflects the degradation of different dimensions of the functional organization of language (Crystal, 1988), namely, the sublexical, lexical semantic and syntactic dimensions; each of these could be subtended by dedicated neural subsystems. A linguistic approach to PPA could bypass the limitation of the a priori grouping of patients into discrete clinical entities and could allow to identify (in each patient) patterns that reflect degradation along various dimensions of language supported by networks that might present different sensitivity to different brain pathologies. Forty-two patients with PPA were studied. We tried to classify them into the principal variants of aphasia according to current standard criteria (Gorno-Tempini et al., 2011), namely, non-fluent, semantic and logopenic. The concept of ‘‘nonfluent’’ production is, however, multidimensional (see Hillis, 2007) and includes features that go beyond agrammatism and apraxia of speech (which are the main features of the so-called nonfluent/agrammatic variant of PPA according to Gorno-Tempini et al., 2011) such as, reduced speech rate or decreased phrase length and word-finding difficulty. On the basis of this evidence we reasoned that nonfluent forms of primary aphasia might not necessarily correspond to apraxia of speech/agrammatism, which is a well-defined clinical syndrome (Harris et al., 2013; Josephs & Duffy, 2008). Thus, apraxia of speech associated with agrammatism was considered a clinical variant, separate from other nonfluent language disorders. Besides clinical classification, we also defined the pattern of each patient’s language disorder according to prevalent involvement of the sublexical, lexical semantic and syntactic levels, respectively. For this purpose, we used a battery of tests devised to explore the status of the different components of the linguistic systems with a cognitive neuropsychological approach (Capasso & Miceli, 2001). The first aim of the study was to confirm (in a population of Italian-speaking aphasic patients) whether primary disorders of language can actually be classified in the proposed discrete clinical entities and then to test whether the corresponding expected brain atrophy patterns can be radiologically detected using visuallyassessed scales that are feasible during routine MRI examinations. Second, we investigated whether the disorganization of language in degenerative pathology reflects nonrandom degradation of language dimensions (Crystal, 1988; Jakobson, 1980), that is, sublexical, lexical semantic and syntactic, and to what extent this degradation contributes (if at all) to the emergence of the main clinical variants of PPA.

2. Materials and methods 2.1. Participants We recruited 42 patients at the Centre for the Medicine of the Aging of the Department of Geriatrics, Neurology and Orthopedics of the Catholic University of Rome, from January 2007 to June

2012. They fulfilled the criteria for PPA (Mesulam, 2001) and underwent a brain MRI scan within a maximum interval of two months from the neuropsychological examination (i.e., either before or after). Patients were included only if they had at least 5 years of formal education, did not express themselves in dialect and completed the neuropsychological examination. We excluded patients with a history or radiological evidence of cerebrovascular diseases (see Neuroimaging) or a history of major psychiatric disorders, alcohol or drug abuse. The experimental group consisted of 40 patients plus two patients with semantic dementia who had been observed before 2007. All patients (and one bilingual subject) were native Italian speakers. All subjects were righthanded. All subjects received a full neuropsychological examination, which included tasks of verbal episodic memory, short-term memory, visuospatial analysis, praxis and intelligence. All patients showed relatively preserved autonomy in the activities of daily living. At least a one-year clinical follow-up was available for 35/42 patients. Samples of spontaneous speech were also collected from 10 matched normal subjects (age: mean = 68.8; sd = 9.23; education: mean: 12.5; sd = 4.60). The study was approved by the Catholic University Institutional Ethics Committee. 2.2. Language examination: tasks and scoring Language was investigated using Capasso and Miceli’s (2001) ‘‘Esame neuropsicologico per l’Afasia-ENPA [Neuropsychological Examination for Aphasia]’’. This test battery aims to detect the presence and severity of language disorders in the different linguistic domains according to cognitive neuropsychological theoretical models of the organization of mental processes (Shallice, 1988). The battery includes a series of tasks that explore the sublexical, lexical semantic and syntactic domains (writing, reading, repetition of non-words (5 items in each task), words (10 items in each task) and sentences (n = 3); oral and written naming of objects and actions (oral naming: n = 10; written naming: n = 5); oral naming of colors (n = 5); comprehension (matching-to-sample) of spoken (n = 20) and written words (n = 20) and sentences (written sentences: n = 14; spoken sentences: n = 14) (sentence/ two-picture matching tasks with semantic, morphological and reversibility distractors); letter (F, A, S) and category (animals, objects, nouns, verbs) fluency. The ENPA language examination takes approximately 60–75 min in one or two consecutive sessions. Each patient’s raw score (number of correct responses) obtained in each task can be adjusted for age and education; the cut-off value is provided. Non-word transcoding evaluates the sublexical mechanisms; transcoding words, naming and single word comprehension evaluate the lexical semantic system. In particular, tasks in which the production of single words is required are supposed to explore the phonological or orthographic output level and the semantic level, whereas tasks requiring the comprehension of single words explore the phonological or orthographic input lexicon and the semantic level. The syntactic grammatical level is explored by reading writing and repetition of sentences as well as by production and comprehension of sentences. Types of errors are also classified and then quantified in each task. In repetition and reading tasks errors are classified as semantic, morphological or phonological and in writing tasks as semantic, morphological and orthographic. Errors produced in naming tasks are classified as semantic, morphological, phonological (or orthographic) and verbal paraphasias, circumlocutions and anomias; in single word comprehension (word-picture matching) errors may be semantic (pointing to the semantic alternative of the item) or phonological (pointing to the phonological alternative). In spoken and written sentence-picture matching tasks there may be errors of reversibility (i.e., violations of the thematic role), morphology

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or semantics. The battery also includes an examination of the number system and calculations. Although we administered the latter tasks, we did not consider the results in the present study. A sample of connected speech, that is, a description of the Cookie Theft Scene (Boston diagnostic aphasia examination) and the Picnic Scene (Western Aphasia Battery), was also recorded for each subject and transcribed. To analyze connected speech, we adopted the criteria provided in the ENPA battery and focused on information, speech rate (number of words/minute), articulation, prosody, presence of embedded sentences, anomias, anomic pauses, conduites d’approche, phonemic and semantic paraphasias, circumlocutions, semantic or phonemic jargon, agreement (article/noun, noun adjective etc.), open class and closed class elements, omissions and substitutions. Effortfulness, hesitations and apraxia of speech (Josephs et al., 2012) were also considered. 2.3. Clinical classification of aphasia Classification of aphasia subtypes was performed by two independent raters (MCS and NC) according to the proposed criteria for the clinical diagnosis of aphasia variants (Gorno-Tempini et al., 2011; Rohrer, Rossor, et al., 2010; Rohrer, Geser, et al., 2010; Whitwell et al., 2013). The classification was performed on clinical grounds and primarily based on the features of speech production; each patient’s performance (scores and errors) in the naming, single word and sentence comprehension tasks of the aphasia battery was also considered. Hypoarticulation and reduced fluency in speech production were the main factors considered for inclusion in the nonfluent aphasia group (NF). However, patients with clear apraxia of speech in which agrammatism was the main feature of the language disorder were eligible for a specific subgroup (apraxia of speech/aphasia – AOS/aph). When hypofluency without an articulatory disorder was associated with anomia, sentence repetition deficits and phonological errors patients were included in the logopenic variant (L); decay of knowledge of words and objects (with semantic errors in naming and single word comprehension and stress errors in reading) in the absence of disorders of speech production and phonological level were the criteria for classification in the semantic variant (S). Raters were requested to force the type of language disorder into one of the four variants or the nonclassified forms (NC). Inter-rater reliability (assessed with Cohen’s Kappa statistics) was relatively high (0.829). When no agreement was reached (5 patients) the decision was made by a third rater (EI).

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production. As word fluency tasks are also influenced by nonlinguistic factors, such as executive abilities, we did not consider them among the tasks sensitive to the lexical semantic deficit. Each task in the battery may explore more than one dimension (e.g., the spoken word comprehension task taps either the phonological input lexicon or the semantic system). Thus, in the tasks that we indicated were sensitive to a specific dimension we considered the score as pathological only if the adjusted value was below the cut-off due to the presence of errors congruent with the dimension explored (see above ‘‘Exploring dimensions of language’’ for classification of errors). For example, word transcoding was considered indicative of a sublexical disorder only if the score was below the cut-off because of phonological/orthographic errors (and not, for example, ‘‘stress’’ or semantic errors). Similarly, naming tasks were considered indicative of lexical semantic disorders only in relation to semantic errors or anomia and not phonological errors. Concerning the syntactic level, in sentence transcoding we considered only omission errors or morphological errors (not phonological/orthographic or semantic errors) and in sentence comprehension we considered only ‘‘reversibility’’ and morphological errors (and not errors in semantic contrasts). The percentage of tasks with pathological scores was then computed for each patient at each level. The presence/absence of agrammatic production was computed for the tasks that explored the syntactic level. A percentage of pathological scores in the 1st quartile (625%) was considered indicative of a mild disorder (severity = 1), in the 2nd quartile (>25% 6 50%) of a moderate disorder (severity = 2), and above the 3rd quartile (>50%) of a severe disorder (severity = 3). 2.5. Measures of patients’ spontaneous speech To provide quantitative measures of patients’ spontaneous speech we evaluated the mean length of utterance-lexical (MLU-L) (mean number of major class items produced in syntactically correct sentences), the mean length of utterance-morphological (MLU-M) (mean number of items produced in syntactically and morphologically correct sentences), speech rate (words/minute = mean number of words produced in three, 1-min samples of andomly selected speech) and percentage of fragments (% of words produced without a recoverable syntactic structure/total words produced) (Miceli, Silveri, Romani, & Caramazza, 1989). The same measures were obtained in samples of connected speech produced by the ten matched controls. 2.6. Neuroimaging

2.4. Exploring dimensions of language Each patient’s performance on the tasks of the ENPA was quantified by two raters (ACB and PR). Types of errors were also classified and quantified in each task. Performance was considered pathological if the adjusted score was below the cut-off of the normative value. To evaluate the status of different dimensions of language in each patient, so that type and severity of the deficit across all patients could be compared, we grouped the tasks as follows: non-word and word transcoding tasks were considered indicative of the efficiency of the sublexical phonological (orthographic) (ph) level. The scores obtained in naming and in single word comprehension tasks were considered indicative of the status of the lexical/semantic level (lex) and those obtained in sentence transcoding (reading, writing and repetition) and sentence comprehension were considered indicative of the syntactic level (sy). To evaluate syntactic level (all tasks in the battery that explore this dimension involve comprehension and repetition of sentences) we also included the presence/absence of agrammatic production (omission of freestanding grammatical morphemes and substitution of bound grammatical morphemes) in spontaneous speech

Images acquisition: Two-dimensional MR images were acquired on 1.5T MR systems (Signa, GE Medical Systems – Milwaukee, US and Achieva, Philips – Best, The Netherlands) using axial Fast Spin Echo or Turbo Spin Echo (FSE or TSE) T1-weighted images, FSE or TSE Coronal T2-weighted images, and FSE or TSE axial T2-weighted Fluid Attenuated Inversion Recovery (T2-FLAIR) images, with the following parameters: slice thickness = 4 mm; gap = 0.4 mm; matrix 512  512; field of view: 270  270 mm; TR/TE = 600/15 (T1-weighted sequences), and 3500–6000/90 ms (T2-weighted sequences); TI = 2000 (T2-FLAIR sequences). Axial images were acquired according to the anterior commissure and posterior commissure plane, and coronal images were acquired orthogonally to this plane. Images analysis: Imaging exclusion criteria included the presence of significant movement or magnetic field artifacts at MRI, incidental findings of intracranial masses, extra-axial fluid collections, post-traumatic parenchymal changes and findings of previous strokes. To exclude patients with significant subcortical cerebrovascular disease, subjects with an age-related white matter changes score >1 and basal ganglia lesions >0 according to the

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Wahlund–Barkhof–Fazekas (WBF) scale (Wahlund et al., 2001), as seen on T2-weighted images, were discarded. Based on these criteria, three patients were excluded because of major movement artifacts on the MR scans and one patient because of a WBF white matter changes score >1. Two expert neuroradiologists (CC and EP, with respectively 25 and 9 years of experience in clinical neuroimaging) who were unaware of the patients’ neurological data and neuropsychological tests results reviewed each examination and provided under consensus atrophy ratings for the anterior temporal lobe (ATL), the anterior frontal lobe (AFL) – including the superior, middle and inferior gyri-, and the temporal-parietal (TP) region for both hemispheres. Atrophy was rated 0 for none/negligible, 1 for moderate and 2 for severe, and asymmetry indexes between the hemispheres were estimated (See detailed procedures described in the Supplementary Methods section). Patterns of atrophy distribution were first evaluated by calculating the average atrophy score of each group in each region of both hemispheres. Furthermore, to identify regions of predominant brain atrophy in each subject, the distribution of the scores obtained from the AFL, ATL and TP regions ratings of both hemispheres was divided into quartiles. The regions whose atrophy score fell beyond the 3rd quartile of this distribution were defined as predominantly atrophic. After blind imaging scoring the patients were divided into S, L NF and AOS/aph variants. The average atrophy scores of each clinical group for each region, together with the percentages of patients in each group with predominant brain atrophy for each brain region, were then represented by histograms and superimposed on anatomic diagrams (Fig. 1A, light-grey and dark-grey bars in histograms, respectively). Average regional atrophy scores and percentages of predominant atrophy were also estimated after grouping patients according to the presence of moderate-to-severe linguistic deficits into the Lex (Lexical semantic), Ph (Phonological/orthographic), Sy (Syntactic), and (Agr) Agrammatic group (See the ‘‘Exploring dimensions of language’’ section) (Fig. 1B). As more than one deficit could be seen in a single subject, patients were assigned to different psycholinguistic categories at the same time, as appropriate (see Section 3.2). 3. Results 3.1. Language: main features of the clinical variants Table 1 shows the distribution of the 42 aphasic patients in the different clinical variants. The table also reports demographic and clinical data. The MMSE score is also reported, even though it is not fully appropriate for quantifying mental deterioration in subjects with language disorders. Table 2 reports the performance (adjusted scores) (type of errors is not considered) obtained by the patients of each variant in the various tasks of the ENPA battery. Table 3 shows type and severity of each subject’s deficit in the various linguistic domains and localization of prevalent atrophy (beyond the 3rd quartile) in each hemisphere. Table 3 also reports each patient’s disease duration, speech rate (words/minute), presence of disorders of articulation and agrammatism, mean length of utterance-lexical (MLU-L), mean length of utterance-morphological (MLU-M) and % of fragmented speech. Mean values of speech rate, MLU-L and MLU-M and % of fragmented speech are also reported for each variant and matched control population. Disease duration was not significantly different in the four clinical variants (Kruskal–Wallis ANOVA by Ranks: H (3, N = 38) = 1.98; p = .57). In the S variant, duration was significantly related to the semantic but not the syntactic deficit (Kendall Tau = 0.47; p < 0.05); in the NF variant, both sublexical and syntactic (but not semantic) disorders were significantly correlated with disease duration (Kendall’s Tau: sublexical: 0.53; p < 0.05; syntactic: 0.41;

p < 0.05). Correlations could not be computed in the other groups because of the low number of observations. One-way ANOVA(df = 3) showed no significant effect of the clinical variant in the production of fragments (F = 1.7; p ns); however, the S patients produced significantly fewer fragments than the NF patients (MannWhitney U test = 2.60; p = 0.009) and all other patients as a group (Mann–Whitney U test = 2.48; p = 0.012). Controls had longer MLU-L and MLU-M than any of the other groups (NC not included) (one-way ANOVA (df = 3): MLU-L F = 5.42; p = 0.001; MLU-M F = 5.07; p = 0.002); no differences emerged among the groups of patients. One-way ANOVA (speech rate as dependent variable) showed a significant effect of group (F = 15.35, df = 4; p < 0.000) (NC not included); controls had a higher speech rate than any of the other groups (LSD test: all p < .000); S longer than L (p < 0.022) and AOS (p < 0.025); no other comparison reached significance. The S variant included a homogeneous group of patients. Differences mostly concerned severity. All patients had a moderate-to-severe lexical semantic deficit; in six patients this was the only deficit; four also had a mild syntactic disorder; and only one (the bilingual patient, no. 6) showed moderate impairment at the syntactic and sublexical level. The pattern was also relatively homogenous in the AOS/aph: overall, severity of aphasia was mild, agrammatism was associated with a mild lexical semantic and a mild-to-moderate syntactic deficit; a mild sublexical disorder was documented in patient 39 (who had a seven-year history and produced some phonemic errors in addition to phonetic distortions). All subjects showed clinical evidence of proper apraxia of speech (Ziegler, Aichert, & Staiger, 2012), and one also showed mild signs of impaired neuromuscular control of speech (dysarthria) (Josephs et al., 2012). By contrast, the NF subjects presented quite heterogeneous disorders. For example, patients 19 showed severe involvement of all three linguistic levels; others, such as patient 30, had quite evident lexical semantic and syntactic disorders but performed normally on the sublexical tasks. Furthermore, only a few patients presented agrammatic production. Several others, such as patient 17, had greatly reduced fluency (but no sign of agrammatism). This can be interpreted in part as a ‘‘high-level’’ planning disorder, which has been shown to occur also in the absence of grammatical and lexical adequacy (Marini et al., 2011) or disorders of articulation characterized by long pauses and extremely simplified, but correct, sentences. Six had mild articulatory disorders; three of them were also agrammatic. The L variant patients showed the expected disorder at the sublexical phonological level. In the L variant, more than in the other subgroups, impairment was widespread in all linguistic dimensions. 3.2. Language: grouping patients on the basis of degradation of linguistic dimensions Grouping patients according to selective degradation of language dimensions was much more difficult than clinical grouping. In fact, except for a few patients who presented a selective lexical semantic deficit, all others were impaired in at least two linguistic domains. But, when we considered each patient’s moderate and severe disorders (not mild ones) most (31/42–74%) were impaired at the lexical semantic level, 19/42–45% at the syntactic level and a few (11/42–26%) at the sublexical level (Table 4). Moreover, when we considered only the selective deficits in the various dimensions of language in each patient, that is, only moderate and severe disorders that were not associated with other moderate or severe disorders in any other dimensions, in 13/42 patients the deficit was semantic and in 3/42 it was syntactic. Patients with selective semantic deficits belonged primarily to the S group (9/11) and

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Fig. 1. (A and B) – Average and predominant regional atrophy patterns in patients stratified according to the criteria for clinical diagnosis of aphasia variants into the S, NF, L and AOS groups (A), and in Ph, Lex, Sy and Agr groups according to the presence of deficits in different dimensions of language (See Methods Section) (B). Non-categorized subjects in A are indicated as ‘‘NC’’. Only patients with moderate-to severe disorders were included in the classification in B. Since more than one linguistic deficit could be seen in a single subject, patients were assigned to different groups categories at the same time (Table 4), if appropriate. Regional atrophy was visually scored on individual MR examinations. For each group/category, light-gray bars in histograms indicate the average score of atrophy in a given region (range 0–2), while dark-gray bars indicate the percentages of cases with predominant atrophy ranks (i.e. beyond the 3rd quartile) in a given brain region: Blue box = Left Anterior Frontal lobe; Light Blue box = Right Anterior Frontal Lobe; Red box = Left Anterior Temporal Lobe; Dark Red box = Right Anterior Temporal Lobe; Green box = Left Temporo-Parietal/BA37 Region; Yellow box = Right Temporo-Parietal/BA37 Region. Each box is superimposed on the corresponding brain region for anatomical reference. Table 1 Distribution of patients according to clinical variants of aphasia. Demographic and clinical data (means, sd and range) are reported for each group of patients. Variants

Male/ Age female (yrs)

Education Disease MMSE (yrs) duration

ADL

IADL

Semantic N = 11

7/4

Logopenic N=3

1/2

Nonfluent N = 21

12/9

AOS/aph N=4

1/3

12.45 4.74 (5–18) 14.33 3.21 (12–18) 11.62 4.58 (5–18) 7.5 2.08 (5–10) 12.66 4.51 (8–17)

5.27 0.79 (4–6) 6 0 (6) 6 0.76 (4–6) 6 0 (0) 5.5 0.71 (5–6)

4.54 2.07 (2–8) 5 2 (3–7) 3 2.28 (1–8) 8 0 (8) 3.5 2.12 (2–5)

Not classified 1/2 N=3

68.36 9.78 (44–78) 73.67 8.14 (68–83) 73.19 6.21 (62–83) 73.5 5.80 (69–82) 76 3.60 (73–80)

2.82 1.25 (2–6) 3 1.73 (2–5) 2.62 0.74 (2–4) 4 2.16 (2–7) 4.33 3.21 (2–8)

20.45 5.64 (10–27) 15.67 4.16 (11–19) 21.28 5.19 (8–29) 26.75 3.95 (21–30) 16.33 7.47 (8–22)

the NF group (3/21), with syntactic deficits to the AOS/aph (1/4) and NF (2/21) groups. In addition, patients with agrammatic production were principally AOS/aph (4/4) and to a lesser extent, NF (3/21).

3.3. Evolution Most patients underwent at least a one-year clinical follow-up. No S (follow-up: 11/11) or L variant (follow-up 3/3) patients presented other neurological signs. In the L variant, the general cognitive deficit was relatively severe, but aphasia remained the dominant clinical feature. Some NF patients (15, 20, 22, and 24) developed mild extrapyramidal signs (three of them had agrammatic production at the time of the experimental examination) (see above). Three/four AOS/aph patients developed Parkinsonism (patients 36 and 39 developed corticobasal degeneration and patient 37 multisystem/olivopontocerebellar atrophy). Overall, although the patients’ aphasia became more severe over time the pattern of their language disorder remained stable. 3.4. Neuroimaging Thirty-three patients presented asymmetrical atrophy with prevalent involvement of the left hemisphere (79%) and a few patients of the right hemisphere (9.5%). In most patients (24/42–57%), atrophy involved the left ATL; in 11/42–26% the left TP area and in 5/42–12% the left AFL (see Table 3). The overall percentages of patients with each clinical variant who presented predominant (i.e. beyond the third quartile) atrophy in the AFL,

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Table 2 Adjusted scores (mean and sd) (type of error is not considered) obtained by the four subgroups of PPA on the tasks of the aphasia battery (ENPA) S = semantic; L = logopenic; AOS/aph = apraxia of speech/aphasia; NC = not classified. Task

N

Cut off

S

L

NF

AOS/aph

NC

Repetition words Repetition nonwords Reading words Reading nonwords Writing words Writing nonwords Oral naming objects Oral naming actions Written naming objects Written naming actions Oral naming colours Comprehension spoken words Comprehension written words Reading sentences Writing sentences Repetition sentences Comprehension spoken sentences Comprehension written sentences Verbal fluency: F,A,S Semantic fluency: ANIMALS Semantic fluency: OBJECTS Grammatical class fluency: NAMES Grammatical class fluency: VERBS

10 5 10 5 10 5 10 10 5 5 5 20 20 2 2 3 14 14

8.8 2 6.4 4 6.3 1.4 8.2 6.1 2.7 3 4 18.4 17 1.3 0.6 3 11.6 11.3 5.43 10.3 8.5 7 5.7

9.73(0.36) 4.55(0.6) 7.17(2.36) 4.68(0.46) 8.03(1.47) 3.77(1.06) 4.23(2.82) 5.14(1.48) 1.35(1.75) 3.45(1.66) 4.14(2.31) 16.7(3.3) 16.67(2.83) 1.81(0.38) 1.27(0.52) 2.71(0.49) 10.93(3.87) 12(1.46) 4.38(3.17) 4.59(3.65) 3.26(3.31) 3.01(3.65) 4.28(5.90)

8.13(0.58) 2.97(1.97) 5.07(4.04) 3.67(1.53) 2.8(2.08) 0.57(0.64) 6(2) 5.47(1.82) 2.87(1.42) 0.57(0.6) 4(1) 19.13(0.64) 17.5(0.78) 1.9(0) 0.2(0.35) 0.67(1.15) 11.3(1.08) 10(1.53) 0.33(0.89) 3.03(2.93) 1.13(1.15) 1.4(6.12) 0.27(4.92)

9.53(1.13) 3.77(1.37) 7.32(2.6) 3.76(1.51) 6.97(1.67) 2.52(1.13) 6.58(2.96) 6.15(2.69) 2.65(1.34) 2.65(1.77) 3.52(1.06) 18.53(1.98) 17.68(2.7) 1.7(0.76) 0.4(0.66) 1.9(1.04) 10.63(2.5) 9.83(3.46) 3.02(2.55) 4.51(3.09) 4.09(3.62) 3.62(3.50) 3.49(4.43)

9.35(1.04) 3.93(1.28) 7.8(3.5) 4.75(0.5) 8.22(1.29) 3.6(1) 10(0) 8.58(1.42) 4.37(1.11) 3.47(1.72) 4.25(0.96) 19.2(1.05) 19.9(0.84) 1.95(0.1) 1.2(0.8) 3(0) 12.83(2.4) 13.28(1.09) 7.66(2.69) 12.3(2.40) 11.02(3.85) 13.25(7.09) 10.32(2.64)

8.13(2.08) 3.73(0.4) 7.4(0) 4.5(0.71) 8.5(2.26) 3.4(0.99) 4.83(3.01) 4.03(3.52) 2.03(2.78) 5.23(5.08) 4(1) 14.87(4.03) 16.63(2.8) 1.27(1.1) 0.4(0.35) 2(1.73) 12.5(1.7) 10.27(2.9) 1.64(1.30) 2.63(3.20) 2.6(4.08) 1.03(1) 1.47(1.40)

ATL and TP regions of each hemisphere are represented in Fig. 1A. The ATL was principally, but not exclusively, involved in the S variant; the anterior (frontal) regions only in NF and AOS/aph. In AOS/aph patients, atrophy was primarily in the left TP region and occasionally extended to the right. When we considered patients with moderate and severe disorders in the various language dimensions and agrammatic production (Fig. 1B), atrophy mostly involved the left ATL, regardless of the linguistic deficit, and to a lesser extent the left TP regions. AFL atrophy was mainly associated with sublexical and syntactic deficits. Unexpectedly, in the presence of agrammatic production atrophy was not limited to the anterior regions. 4. Discussion 4.1. Clinical variant of PPA Thirty-five out of 42 patients could be clinically classified as having the S, L and NF variants (Gorno-Tempini et al., 2011); four had AOS/aph; three patients could not be placed in any recognizable syndrome. Patients in all groups were formally hypofluent compared to controls if we consider MLU and speech rate. However, the S patients had a significantly longer speech rate compared to the L and NF patients and produced fewer fragments. Patients with the S variant presented a relatively homogenous pattern of deficits with at least a moderate lexical semantic disorder. Some S patients also presented mild syntactic disorders. Only errors in reversibility and morphological (but not semantic) distractors were computed to quantify the syntactic deficit; thus, the patients’ decay in these tasks was to some extent unexpected. However, sentence comprehension is a relatively complex task that can also be influenced by nonlinguistic factors such as attention, working memory or picture processing. Patients with AOS/aph also showed a relatively consistent pattern: they did not produce phonological errors (only phonetic distortions) but had mild lexical semantic and syntactic deficits and agrammatic production. Two of them also had a rather homogeneous pattern of phonological short-term memory impairment (Silveri & Baldonero, 2013). The NF patients seemed to be a very heterogeneous subgroup (Silveri & Ciccarelli,

2007a), with a less clear-cut pattern of linguistic disorders than both the S variant and the AOS/aph. Only some of the NF aphasic patients showed involvement of the sublexical level and only a very few showed agrammatic production; some also had mild hypoarticulation. Regardless of disease duration, the L aphasic patients had the most severe language impairment. It involved all language dimensions including the sub-lexical level, which by contrast was less impaired in aphasic patients belonging to the other subgroups. No L patients had agrammatic production or articulatory disorders despite their relatively severe hypofluency (Gorno-Tempini et al., 2011; Rohrer, Rossor, et al., 2010). The L aphasic group was much smaller than in earlier studies (Fraser et al., 2012; Wilson et al., 2010). This finding is consistent with previous evidence (Sajjadi, Patterson, Arnold, Watson, & Nestor, 2012) and suggests a bias in classification. As the raters were required to separate the patients into four groups, it is conceivable that those included in the NF variant were to some extent the ones who could not be classified in the S variant or the AOS/aph, whose core features represent more distinguishable patterns; the L variant might represent a more severe form of NF aphasia, that is, the type without articulatory deficits or agrammatic production but with more evident phonological disorders. The heterogeneity of the NF aphasic patients in our sample might thus reflect the bias deriving from the classification criteria. Previous classifications (Gorno-Tempini et al., 2011) did not explicitly consider patients who fit the AOS/aph criteria, and just apraxia of speech or just agrammatism was sufficient to include patients in the NF variant. In our sample, once we identified the AOS/aph with more restricted criteria and the S variant, most of the remaining patients were placed in the NF group; and in this group, the L patients might represent those whose disorders at the phonemic level were more evident. In other words, the NF and L aphasic patients might have been classified on the basis of the absence of features that better characterized the patients in the other two groups, and the L patients might be those with the most severe sublexical phonological disorders. Alternatively, all non-fluent subjects in our sample who did not present with clear apraxia of speech and agrammatism could fall within the logopenic group. But the main characteristics of the logopenic variant (Gorno-Tempini et al., 2011) were not observed

Table 3

Type, severity of the linguistic deficit, clinical diagnosis (variant) and neuroimaging data (prevalent atrophy: beyond 3rd quartile) in the 42 PPA patients. 0 = no deficit; 1 = mild; 2 = moderate; 3 = severe. Duration yrs

% MLU-L Fragments

MLU-M

Speech rate

Sublexical phonological deficit

Lexical semantic deficit

Syntactic deficit

Clinical Prevalent diagnosis atrophy

Predominant atrophy

Patient Duration yrs

% MlU-S Fragments

MLU-M

Speech Rate

Sublexical phonological deficit

Lexical semantic deficit

Syntactic deficit

Clinical Prevalent diagnosis atrophy

Predominant atrophy

1 2 3 4 5 6 7 8 9 10 11 Mean (SD)

3 3 2 2 2 3 6 3 2 3 2

7 8 0 8 0 5 0 0 0 9 5 3.82 (3.84)

3.92 5 6.8 5.5 4.68 5 4.1 7 5.8 3 3.71 4.95 (1.23)

3.90 5 6.8 5.3 4.60 5 4.1 7 5.8 3 3.7 4.93 (1.26)

76.5 57 62.5 50.5 50 84 57 92.5 106.5 56 58 68.6 (31.9)

0 0 0 0 0 2 0 0 0 0 0

3 3 3 2 3 3 3 2 2 3 3

1 1 0 0 0 2 0 0 0 1 2

S S S S S S S S S S S

l/T l/T-P l/r-T _c l/T l/T l/T l/T-P l/r-T l/T-P l/ r-T

L L R L L L L L L L R

22 23 24 25 26 27 28 29 30 31 32 33

3 2 4 2 2 2 2 3 2 4 3 3

3 13 0 15 10 0 2 11 7 7 8 16

3.2 6 1 5.2 4 4.6 5.5 5 5.7 5.1 4.8 5.4

3.2 6 1 5.2 4 4.6 5.6 5 5.7 5.1 4.8 5.2

60.5a,b 56b 20a,b 82.5 80 88.6 33.5 60 87.5 49.5b 59 89

1 0 2 0 0 0 0 2 0 2 0 1

3 2 3 2 2 1 1 3 3 2 1 3

2 1 3 1 1 1 0 2 2 1 0 2

NF NF NF NF NF NF NF NF NF NF NF NF

l/T-P r/T l/r-F _c l/T _c _c l/F-T l/T l/r-T l/F l/T

L R L – L – – L L L L L

12 13 14

2 5 2

19 6 8

4 4.27 3.4

4 4.1 3.4

24 17 64

2 3 3

3 2 3

2 2 2

L L L

l/T-P _c l/T

L L L

34 35 Mean (SD)

2 3

0 22 11.1 (9.19)

4.9 5.1 4.38 (1.27)

4.9 5.1 4.37 (1.26)

38.5 49b

0 0

2 0

2 2

NF NF

l/P r/l-T

L –

11.0 (7.0)

3.89 (0.45)

3.83 (0.38)

35.0 (25.4)

36

2

3

5.6

5.6

30.3a,b

0

1

1

AOS

l/P

L

Mean (SD) 15 16 17 18

3 2 2 3

10 19 29 11

4.05 5.27 3 3.4

4 5.27 2.8 3.4

87.3 55 24.5 63.5a,b

1 0 2 1

2 1 3 3

3 1 2 3

NF NF NF NF

l/T l/T-P l/F-T l/T-P

L L L L

37 38 39 Mean (SD)

2 2 7

1 34 51 10.50 (15.7)

5.7 4 2 4.32 (1.73)

5.7w 4.1 2 4.35 (1.73)

36.6a,b 79.5a,b 10a,b

0 0 1

1 1 1

1 1 2

AOS AOS AOS

r/l-T l/F l/r-P

19 20 21

4 2 2

38 60 15

3.2 2.5 5.4

3.2 2.5 5.4

38 43.6a 58

2 2 1

3 3 1

3 1 2

NF NF NF

l/P _c _c

L L L

40 41 42

8 3 2

51 41 14

2.5 3.9 5.2

2 3.8 5.2

60.5 52 40

2 0 0

3 1 3

2 0 1

NC NC NC

_c _c r/T

L L –

L – R

Matched normal subjects (n = 10): mean (sd) of % fragments: