Novel clinical, molecular and bioinformatics insights into the genetic background of autism.

BACKGROUND: Clinical classification of autistic patients based on current WHO criteria provides a valuable but simplified depiction of the true nature of the disorder. Our goal is to determine the biology of the disorder and the ASD-associated genes that lead to differences in the severity and variability of clinical features, which can enhance the ability to predict clinical outcomes. METHOD: Novel Whole Exome Sequencing data from children (n = 33) with ASD were collected along with extended cognitive and linguistic assessments. A machine learning methodology and a literature-based approach took into consideration known effects of genetic variation on the translated proteins, linking them with specific ASD clinical manifestations, namely non-verbal IQ, memory, attention and oral language deficits. RESULTS: Linear regression polygenic risk score results included the classification of severe and mild ASD samples with a 81.81% prediction accuracy. The literature-based approach revealed 14 genes present in all sub-phenotypes (independent of severity) and others which seem to impair individual ones, highlighting genetic profiles specific to mild and severe ASD, which concern non-verbal IQ, memory, attention and oral language skills. CONCLUSIONS: These genes can potentially contribute toward a diagnostic gene-set for determining ASD severity. However, due to the limited number of patients in this study, our classification approach is mostly centered on the prediction and verification of these genes and does not hold a diagnostic nature per se. Substantial further experimentation is required to validate their role as diagnostic markers. The use of these genes as input for functional analysis highlights important biological processes and bridges the gap between genotype and phenotype in ASD.

SPECT analysis and language profile in Greek speaking patients with subtypes of frontotemporal dementia.

OBJECTIVE: We aimed to examine if single photon emission computed tomography (SPECT) can discriminate between variants of frontotemporal dementia (FTD). As a secondary investigation we identify and establish the linguistic differences between those variants. MATERIALS AND METHODS: Nine patients with semantic variant primary progressive aphasia (svPPA), 8 with non-fluent variant primary progressive aphasia (nfvPPA) and 17 with behavioral variant of frontotemporal dementia (bvFTD) were compared on Addenbrooke's cognitive examination-revised (ACE-R), auditory comprehension, oral expression and verbal fluency. All patients were also compared with healthy controls. Patients were evaluated using technetium-99m-hexamethylproyleneamine oxime (99mTc-HMPAO) brain SPECT as a measure of regional cerebral flow. RESULTS: Significant group differences between all patients and controls were found for ACE-R, auditory comprehension and oral expression. Semantic variant primary progressive aphasia patients performed higher in letter compared to category fluency with significant deficits in auditory comprehension and oral expression. Non-fluent variant primary progressive aphasia patients showed significant deficits in auditory comprehension but not oral expression while performed lightly worse in letter fluency compared to category. Behavioral variant of frontotemporal dementia patients showed deficits in auditory comprehension and oral expression and performed similar in category and letter fluency. Single photon emission computed tomography analysis revealed left frontotemporal hypoperfusion extending to the right frontotemporal region in svPPA patients. Non-fluent variant primary progressive aphasia patients presented left frontotemporal hypoperfusion with participation of the left parietal and right frontotemporal regions. Behavioral variant of frontotemporal dementia patients showed bilateral frontotemporal hypoperfusion compared to parietal and visual cortices. CONCLUSION: Our findings suggest that SPECT may assist in the discrimination of the FTD variants. We also confirmed that bvFTD patients share similar language deficits with svPPA patients.

Semantic fluency difficulties in developmental dyslexia and developmental language disorder (DLD): poor semantic structure of the lexicon or slower retrieval processes?

BACKGROUND: Children with dyslexia and/or developmental language disorder (hereafter children with DDLD) have been reported to retrieve fewer words than their typically developing (TD) peers in semantic fluency tasks. It is not known whether this retrieval difficulty can be attributed to the semantic structure of their lexicon being poor or, alternatively, to words being retrieved more slowly despite semantic structure being intact. AIMS: To test two theoretical models that could potentially account for retrieval difficulties in semantic fluency tasks, namely, the Poor Lexical-Semantic Structure Model and the Slow-Retrieval Model. Both models predict that children with DDLD will retrieve fewer items compared with TD children. However, while the Poor Lexical-Semantic Structure Model predicts a less sophisticated network of semantic connections between words in the lexicon, as evidenced by smaller clusters of related items in children with DDLD, the Slow-Retrieval Model predicts intact inter-item associations in the lexicon, as evidenced by the two groups' clusters being of a similar size. The groups' semantic fluency performance was therefore compared. How semantic fluency performance related to children's language, literacy, and phonological skills was also investigated. METHODS & PROCEDURES: A total of 66 children with DDLD aged 7-12 years and 83 TD children aged 6-12 years, all monolingual Greek speakers, were tested on semantic fluency, using the categories 'animals', 'foods' and 'objects from around the house'. The numbers of correct and incorrect responses, clusters and switches, and the average cluster size were computed. Children were also assessed on non-verbal IQ, language, literacy and phonological tasks. OUTCOMES & RESULTS: In both groups, productivity in semantic fluency tasks correlated strongly with the numbers of clusters and switches, but not with average cluster size. The DDLD group produced significantly fewer correct responses and fewer clusters compared with the TD group, but the two groups showed similar switching and average cluster size. Children's language, literacy and phonological skills significantly predicted the number of correct responses produced, beyond the significant effect of age. CONCLUSIONS & IMPLICATIONS: We conclude that poorer semantic fluency performance in children with DDLD results not from a lexicon with poor semantic structure, but rather from slower retrieval processes from a lexicon with intact semantic structure. The underlying causes of slow lexical retrieval still need further investigation.

Time reference, morphology and prototypicality: tense production in stroke aphasia and semantic dementia in Greek.

The present study aims at investigating verb inflection in aphasia and semantic dementia. In particular, it addresses the contribution of time reference and morphological complexity. Moreover, it investigates whether the lexical properties of the verb, such as argument structure and lexical aspect interact with the production of tense. Ten individuals with (different types of) stroke aphasia and five individuals with semantic dementia and their respective control groups conducted a sentence completion task. Three tenses were tested: past perfective, past imperfective and present. All tenses had to be produced with three different verb classes, which differed with respect to syntactic and semantic properties: unergative, unaccusative and transitive verbs. The findings imply problems with marking aspect and an interaction between inflection and lexical aspect but no effect of morphological complexity or across the board difficulties with reference to the past in aphasia. Moreover, the results suggest problems with inflection in semantic dementia, an interaction between inflection and lexical aspect and a selective difficulty with imperfective tenses. The study contributes to a better understanding of inflection problems in aphasia and it provides evidence for inflection problems in semantic dementia.

Cognitive vs. Linguistic Training in Children with Developmental Language Disorder: Exploring Their Effectiveness on Verbal Short-Term Memory and Verbal Working Memory.

The present study explores comparatively the effectiveness of a cognitive (verbal short-term memory (vSTM), verbal working memory (vWM)) and of a linguistic training (10-week duration each) in the diffusion of gains in cognitive abilities (vSTM and vWM) of in school-aged Greek-speaking children with developmental language disorder (DLD). To this purpose, two computerized training programs i.e., a linguistic and a cognitive one, were developed and applied to three groups (A, B, and C) of children with DLD (N = 49, in total). There were three assessments with two vSTM tasks (non-word repetition and forward digit span) and a vWM task (backward digit span): pre-therapeutically (time 1), where no significant between-group differences were found, post-therapeutically I (time 2), and post-therapeutically II (time 3) and two training phases. In phase Ι, group A received meta-syntactic training, whereas group B vSTM/vWM training and group C received no training. In phase ΙΙ, a reversal of treatment was performed for groups A and B: group A received vSTM/vWM while group B meta-syntactic training. Again, group C received no training. Overall, the results indicated a significant performance improvement for the treatment groups and revealed beneficial far-transfer effects as language therapy can affect vSTM and vWM in addition to direct and near transfer effects. In addition, the intervention type order affected performance as follows: first, better performance on the vSTM task (non-word repetition) was shown when the linguistic treatment was delivered first; second, better performance on the vWM in Time 2 and Time 3 was shown by group B, for which the cognitive treatment was delivered first. Concluding, not only intervention type but also intervention type order can affect performance in DLD.

Morphosyntactic Abilities and Cognitive Performance in Multiple Sclerosis.

While cognitive abilities in people with multiple sclerosis (PwMS) have been studied in detail, little is known about linguistic abilities in PwMS and their relation to cognitive impairment. In this cross-sectional explorative study, we aim to investigate the morphosyntactic abilities of PwMS alongside their cognitive performance. Furthermore, we explore the effect of clinical factors, namely, the disease duration and MS type, on the linguistic and cognitive performance of PwMS. By so doing, we aim to shed light on neurocognitive and clinical correlates of linguistic performance in PwMS. We included 78 patients and 78 age-, sex- and education-matched healthy individuals. All participants were additionally administered the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) battery, a verbal short-term memory task (non-word repetition) and questionnaires about mood, fatigue and quality of life. In addition, they underwent examinations with morphology and syntax tasks. PwMS were found to be impaired in morphology (past tense) and selectively impaired in syntax alongside cognitive impairments. Disease duration had the main impact on cognitive abilities. The MS type selectively impacted linguistic abilities, as shown by the remarkably deficient performance of the MS individuals with the progressive disease subtype. Linguistic impairments were predicted by only one measure of the BICAM test, namely, the Symbol Digit Modalities Test (SDMT), a measure of cognitive processing speed. Overall, this study contributes to the better understanding of the linguistic profile of PwMS by reporting selective deficits in their morphological and syntactical abilities. Furthermore, it provides insights into the clinical and cognitive correlates of linguistic performance. By so doing, it suggests clinical implications for the development of intervention programs for PwMS.

The psychometric properties of the Greek version of the Social Communication Questionnaire.

There is a scarcity of diagnostic assessments and screening tools for autism spectrum disorders (ASD) in Greek. In this study, we examined the psychometric properties of the recently developed Greek version of the Social Communication Questionnaire (SCQ). We used parental responses for 311 children (mean age: 7.54 years old, SD = 1.92), 122 with a diagnosis of ASD (93 boys, 29 girls) and 189 neurotypical children (104 boys, 85 girls), with 167 responses referring to the Lifetime and 144 to the Current form of the SCQ. Both forms presented adequate construct validity based on the four-factor model, while in both forms, autistic children presented higher SCQ total and subscale scores (four factors) than typical children. The forms had excellent internal reliability. An item-response-theory analysis suggested that over 80% of test items fitted adequately a Rasch model, while a preliminary analysis of gender biases suggested that a small number of items (Lifetime: five; Current: six out of 39) were differentially sensitive to autistic symptomatology in boys and girls. A receiver-operating-characteristic analysis showed excellent diagnostic performance based on the SCQ total score (Lifetime: area-under-the-curve/AUC = 0.937, Current: AUC = 0.963), and acceptable to excellent discrimination for the four subscales (AUCs between 0.737 and 0.955). Our preliminary results suggest that the Greek SCQ presents satisfactory psychometric properties and can be used for differentiating children with ASD from typical children in initial assessments within clinical and research settings. LAY SUMMARY: Autism spectrum disorder (ASD or autism) is a lifelong neurodevelopmental condition with a prevalence of ~1.5%-2% and characterized by difficulties in social interaction and communication and repetitive and restricted behaviors. There is increasing concern that research in ASD has focused on a small number of languages and cultural settings and that this bias challenges the identification and diagnosis of the condition in other languages and cultures, which are underrepresented in autism research. One such language is Greek (spoken by ~13.5 million), for which there is a scarcity of standardized instruments for the diagnosis of autism. This study examines the psychometric properties of the recently published Greek version of the Social Communication Questionnaire (SCQ), a widely used screening tool for ASD. We conduct an in-depth psychometric analysis of the Greek SCQ, including both forms in which the instrument is available (Lifetime and Current). This analysis shows that the Greek SCQ can be used for differentiating children with ASD from typical children in initial assessments within clinical and research settings. The findings of this study have implications for clinicians, special educators and researchers working with Greek-speaking individuals with ASD and, more broadly, for cross-cultural autism research.

Assessing phonological short-term memory in Greek: Reliability and validity of a non-word repetition test.

This study explores the reliability and validity of a NWR task in a large cohort of 387 TD Greek-speaking children aged 7-13 years attending elementary (Grades 2-6) and secondary school (Grade 1), divided into six age groups. Further, the relationship between NWR and reading fluency skills as well as the predictive value of the NWR on reading fluency skills in TD children are examined. To investigate the external reliability of the NWR task, test-retest reliability was performed, and excellent test-retest reliability was found. Internal reliability was explored with Cronbach's alpha coefficient and good reliability was found. To explore convergent validity, correlation analysis between NWR and reading fluency was conducted and significant and strong correlations were found for all age groups excepted 2 (ages 9-10 and 12-13). To examine predictive validity, regression analysis was conducted between these two variables and showed that performance on NWR contributed significantly to reading fluency skills, suggesting that NWR skills are a good predictor of reading skills. Finally, it was explored whether the relevant scores increase as a function of age and found significant differences between groups that differed in 2 years or more, while this difference was no longer significant after 10 years. This finding suggests that phonological STM increases in capacity along with age, but only until the age of 10, where it seems to reach a ceiling. In addition, linear regression analysis showed that age contributed significantly to performance on NWR test. To sum up, the present study provides normative data of a NWR test for a wide age range, which does not exist in the Greek language (particularly for ages over 9 years) and it can be concluded that the present NWR test can be successfully used as a reliable and valid measure of phonological STM in the age range that was examined in this study.

Subject-verb agreement, object clitics and wh-questions in bilingual French-Greek SLI: the case study of a French-Greek-speaking child with SLI.

In this study we investigate the linguistic performance of a school age French-Greek simultaneous bilingual boy with specific language impairment (SLI) on the production of subject-verb agreement, object clitic pronouns and wh-questions. In addition, we compare his performance on these linguistic structures with that of two French-Greek bilingual children with typical development matched on language age. Furthermore, we discuss the performance of the child with SLI in the light of published data from monolingual French and Greek school-age children with SLI, as reported in the relevant literature. The results indicated that the performance of the bilingual French-Greek-speaking child with SLI was highly comparable to that of bilingual French-Greek typically developing children and monolingual children with SLI speaking French or Greek. In addition, the results revealed a language effect on the performance of the bilingual child with SLI on subject-verb agreement, object clitics and wh-questions. We adopt a comparative linguistic approach to interpret the results and argue that the specific linguistic properties of Greek and French were significant determinants for the manifestation of SLI in each language. We suggest that bilingualism per se did not aggravate the language deficits in this child with SLI. Finally, we discuss the clinical implications of our study for language intervention in bilingual individuals with SLI.

Production and comprehension of pronouns by Greek children with specific language impairment.

This study contributes to the characterization of the deficit in specific language impairment (SLI) by investigating whether deficits in the production and comprehension of pronouns in Greek children with SLI are best accounted for by domain-general or domain-specific models of the language faculty. The Greek pronominal system distinguishes between acoustically salient and non-salient forms, which are both interpreted on semantic/thematic grounds, and non-salient forms (object clitics) interpreted on syntactic grounds either in spec-head agreement or syntactic dependencies incurring feature checking through movement/chain formation. The results revealed a significant effect of the syntactic configuration on the production and comprehension of object clitics. Children with SLI were significantly impaired in the production and comprehension of those clitics that enter into operations necessitated by complex syntactic dependencies involving feature checking through movement/chain formation. Thus, the data support the computational grammatical complexity hypothesis and indicate that the deficits associated with object clitics in Greek-speaking children with SLI result from domain-specific impairment with syntactic dependencies incurring feature checking at the clause level involving movement/chain formation.

Lexical and Grammatical Factors in Sentence Production in Semantic Dementia: Insights From Greek.

Purpose: Language production in semantic dementia (SD) is characterized by a lexical-semantic deficit and largely preserved argument structure and inflection production. This study investigates (a) the effect of argument structure on verb retrieval and (b) the interrelation between inflection marking and verb retrieval in SD. Method: Seven individuals with SD and 7 healthy controls performed 2 sentence elicitation tasks. In Experiment 1, participants described the action taking place in a video. In Experiment 2, they watched the same videos preceded by a phrase prompting the production of past tense. Three verb classes were tested: (a) unergative (e.g., to walk), (b) unaccusative (e.g., to fall), and (c) transitive with 1 object (e.g., to read a book). Results: There was not any quantitative difference among the verb classes in Experiment 1, but error analysis hinted at difficulties related with argument structure complexity. The findings of Experiment 2 suggest no general effect of inflection on verb retrieval; nevertheless, inflection marking impeded the retrieval of verbs with complex argument structure. Large individual variation was established. Conclusions: Argument structure complexity may challenge speakers with SD. Verb retrieval and inflection marking seem to interrelate at the expense of the former. Inflection production may be affected at severe stages of the disease. Supplemental Material: https://doi.org/10.23641/asha.6030779.

Clause structure and verb movement in a Greek-English speaking bilingual patient with Broca's aphasia: evidence from adverb placement.

In this paper, we investigate the performance of a Greek-English bilingual patient with Broca's aphasia and mild agrammatism on the placement of CP, MoodP, AspectP, and NegP-related adverbs, labeled specifier-type adverbs, and VP-related adverbs, labeled complement-type adverbs, by means of a constituent ordering task and a grammaticality judgment task. Based on the results derived by means of these two different tasks in both Greek and English, we argue that (i) the CP layer causes great difficulties to aphasic performance in both languages but it is not missing from aphasic grammar, whereas the VP layer remains intact in both languages; (ii) the MoodP, AspectP, and NegP-related adverbs cause more difficulties in English that in Greek. We attribute this to the independent differences between English and Greek that relate to properties of verbal morphology and syntactic head movement.

Morphological cues in the comprehension of relative clauses by Greek children with specific language impairment and typical development: A comparative study.

PURPOSE: This study investigated the effect of morphological case and number marking on the comprehension of relative clauses by Greek children with Specific Language Impairment and Language Age controls. METHOD: An agent selection task and experimental materials consisting of 12 subject and 12 object relative clauses were employed. There were two experimental conditions: The first one manipulated number marking for Noun Phrases and the verb (singular vs plural) and neutralised Case through the use of Noun Phrases with neuter gender, which in Greek is ambiguous between Nominative and Accusative. The second one manipulated case and included Noun Phrases marked for morphological case. RESULT: The Language Age controls performed better on the comprehension of object relative clauses with case manipulation than on those with number, unlike the children with Specific Language Impairment, who performed at the same level on the comprehension of relative clauses with number and case manipulation. CONCLUSION: The children with Specific Language Impairment did not make efficient use of the morphological case cues in object relative clause interpretation. We argue that deficient use of case cues in object relative clause interpretation is due to difficulties in rapid interpretation of case information in these demanding structures.

Functional categories in agrammatism: evidence from Greek.

The aim of this study is twofold. First, to investigate the use of functional categories by two Greek agrammatic aphasics. Second, to discuss the implications of our findings for the characterization of the deficit in agrammatism. The functional categories under investigation were the following: definite and indefinite articles, personal pronouns, aspect, tense, subject-verb agreement, wh-pronouns, complementizers and the mood marker na (=to). Based on data collected through different methods, it is argued that the deficit in agrammatism cannot be described in terms of a structural account but rather by means of difficulties in the implementation of grammatical knowledge.

Working memory and verbal fluency in simultaneous interpreters.

We investigated working memory and verbal fluency in simultaneous interpreters, expecting to find enhanced working memory and semantic processing in interpreters relative to others fluent in a second language. The interpreters (n = 15) outperformed the control group (n = 35) on semantic fluency and most measures of working memory; their advantage over teachers of a foreign language (n = 15) approached, but did not reach, statistical significance. Our findings suggest that, while proficiency in a foreign language may enhance fluency and working memory skills, simultaneous interpreters have semantic processing and working memory capacities greater than those expected from mere proficiency in a foreign language.

The perfective past tense in Greek child language.

This study examines the perfective past tense of Greek in an elicited production and an acceptability judgment task testing 35 adult native speakers and 154 children in six age groups (age range: 3 ; 5 to 8 ; 5) on both existing and novel verb stimuli. We found a striking contrast between sigmatic and non-sigmatic perfective past tense forms. Sigmatic forms (which have a segmentable perfective affix (-s-) in Greek) were widely generalized to different kinds of novel verbs in both children and adults and were overgeneralized to existing non-sigmatic verbs in children's productions. By contrast, non-sigmatic forms were only extended to novel verbs that were similar to existing non-sigmatic verbs, and overapplications of non-sigmatic forms to existing sigmatic verbs were extremely rare. We argue that these findings are consistent with dual-mechanism accounts of morphology.