Endophenotyping social cognition in the broader autism phenotype.

Relatives of individuals with autism spectrum disorder (ASD) may display milder social traits of the broader autism phenotype (BAP) providing potential endophenotypic markers of genetic risk for ASD. We performed a case-control comparison to quantify social cognition and pragmatic language difficulties in the BAP (n = 25 cases; n = 33 controls) using the Faux Pas test (FPT) and the Goldman-Eisler Cartoon task. Using deep phenotyping we then examined patterns of inheritance of social cognition in two large multiplex families and the spectrum of performance in 32 additional families (159 members; n = 51 ASD, n = 87 BAP, n = 21 unaffected). BAP individuals showed significantly poorer FPT performance and reduced verbal fluency with the absence of a compression effect in social discourse compared to controls. In multiplex families, we observed reduced FPT performance in 89% of autistic family members, 63% of BAP relatives and 50% of unaffected relatives. Across all affected families, there was a graded spectrum of difficulties, with ASD individuals showing the most severe FPT difficulties, followed by the BAP and unaffected relatives compared to community controls. We conclude that relatives of probands show an inherited pattern of graded difficulties in social cognition with atypical faux pas detection in social discourse providing a novel candidate endophenotype for ASD.

Individual Differences in Intrinsic Brain Networks Predict Symptom Severity in Autism Spectrum Disorders.

The neurobiology of heterogeneous neurodevelopmental disorders such as Autism Spectrum Disorders (ASD) is still unknown. We hypothesized that differences in subject-level properties of intrinsic brain networks were important features that could predict individual variation in ASD symptom severity. We matched cases and controls from a large multicohort ASD dataset (ABIDE-II) on age, sex, IQ, and image acquisition site. Subjects were matched at the individual level (rather than at group level) to improve homogeneity within matched case-control pairs (ASD: n = 100, mean age = 11.43 years, IQ = 110.58; controls: n = 100, mean age = 11.43 years, IQ = 110.70). Using task-free functional magnetic resonance imaging, we extracted intrinsic functional brain networks using projective non-negative matrix factorization. Intrapair differences in strength in subnetworks related to the salience network (SN) and the occipital-temporal face perception network were robustly associated with individual differences in social impairment severity (T = 2.206, P = 0.0301). Findings were further replicated and validated in an independent validation cohort of monozygotic twins (n = 12; 3 pairs concordant and 3 pairs discordant for ASD). Individual differences in the SN and face-perception network are centrally implicated in the neural mechanisms of social deficits related to ASD.

Individualised MRI training for paediatric neuroimaging: A child-focused approach.

Magnetic Resonance Imaging (MRI) in paediatric cohorts is often complicated by reluctance to enter the scanner and head motion-related imaging artefacts. The process is particularly challenging for children with neurodevelopmental disorders where coping with novel task demands in an unfamiliar setting may be more difficult due to symptom-related deficits or distress. These issues often give rise to excessive head motion that can significantly reduce the quality of images acquired, or render data unusable. Here we report an individualised MRI training procedure that enables children with Autism Spectrum Disorders (ASD) to better tolerate the MRI scanner environment based on a child-focused approach and individualised familiarisation strategies, including a pre-visit interview, familiarisation package, and personalised rewards. A medical imaging mobile application was utilised to familiarise participants to multi-sensory aspects of the neuroimaging experience through a variety of themed mini-games and activities. The MRI training procedure was implemented for monozygotic twins (n = 12; 6 twin pairs; age range 7.1-12.9 years) concordant or discordant for ASD. MRI image quality indices were better or comparable to images acquired from a large independent multi-centre ASD cohort. Present findings are promising and suggest that child-focused strategies could improve the quality of paediatric neuroimaging in clinical populations.

Quantifying individual differences in brain morphometry underlying symptom severity in Autism Spectrum Disorders.

The neurobiology of heterogeneous neurodevelopmental disorders such as autism spectrum disorders (ASD) are still unclear. Despite extensive efforts, most findings are difficult to reproduce due to high levels of individual variance in phenotypic expression. To quantify individual differences in brain morphometry in ASD, we implemented a novel subject-level, distance-based method on subject-specific attributes. In a large multi-cohort sample, each subject with ASD (n = 100; n = 84 males; mean age: 11.43 years; mean IQ: 110.58) was strictly matched to a control participant (n = 100; n = 84 males; mean age: 11.43 years; mean IQ: 110.70). Intrapair Euclidean distance of MRI brain morphometry and symptom severity measures (Social Responsiveness Scale) were entered into a regularised machine learning pipeline for feature selection, with rigorous out-of-sample validation and permutation testing. Subject-specific structural morphometry features significantly predicted individual variation in ASD symptom severity (19 cortical thickness features, p = 0.01, n = 5000 permutations; 10 surface area features, p = 0.006, n = 5000 permutations). Findings remained robust across subjects and were replicated in validation samples. Identified cortical regions implicate key hubs of the salience and default mode networks as neuroanatomical features of social impairment in ASD. Present results highlight the importance of subject-level markers in ASD, and offer an important step forward in understanding the neurobiology of heterogeneous disorders.

Different brain networks underlying intelligence in autism spectrum disorders.

There has been sustained clinical and cognitive neuroscience research interest in how network correlates of brain-behavior relationships might be altered in Autism Spectrum Disorders (ASD) and other neurodevelopmental disorders. As previous work has mostly focused on adults, the nature of whole-brain connectivity networks underlying intelligence in pediatric cohorts with abnormal neurodevelopment requires further investigation. We used network-based statistics (NBS) to examine the association between resting-state functional Magnetic Resonance Imaging (fMRI) connectivity and fluid intelligence ability in male children (n = 50) with Autism Spectrum Disorders (ASD; M = 10.45, SD = 1.58 years and in controls (M = 10.38, SD = 0.96 years) matched on fluid intelligence performance, age and sex. Repeat analyses were performed in independent sites for validation and replication. Despite being equivalent on fluid intelligence ability to strictly matched neurotypical controls, boys with ASD displayed a subnetwork of significantly increased associations between functional connectivity and fluid intelligence. Between-group differences remained significant at higher edge thresholding, and results were validated in independent-site replication analyses in an equivalent age and sex-matched cohort with ASD. Regions consistently implicated in atypical connectivity correlates of fluid intelligence in ASD were the angular gyrus, posterior middle temporal gyrus, occipital and temporo-occipital regions. Development of fluid intelligence neural correlates in young ASD males is aberrant, with an increased strength in intrinsic connectivity association during childhood. Alterations in whole-brain network correlates of fluid intelligence in ASD may be a compensatory mechanism that allows equal task performance to neurotypical peers.

Screening Bilingual Preschoolers for Language Difficulties: Utility of Teacher and Parent Reports.

Purpose: The utility of parent and teacher reports for screening 3 types of bilingual preschoolers (English-first language [L1]/Mandarin-second language[L2], Mandarin-L1/English-L2, or Malay-L1/English-L2) for language difficulty was investigated in Singapore with reference to measures of reliability, validity, sensitivity, and specificity in an English-medium kindergarten setting. Method: The index tests were teachers' ratings of the English language ability of 5-year-olds (N = 85) on the Bilingual Language Assessment Battery (BLAB): Preschool Teacher Report (Pua, Lee, & Rickard Liow, 2013) and parents' ratings of their child's home language ability (N = 78 English-L1, Mandarin-L1, or Malay-L1) on the BLAB: Preschool Parent Report (Pua, Lee, & Rickard Liow, 2013). The reference standards were objective measures of single-word receptive vocabulary (80 items) and expressive vocabulary (140 items) in the child's L1 and L2, as proxies for language ability. Results: BLAB Teacher Reports for the English receptive and expressive subscales showed concurrent validity for all 3 bilingual groups, as well as generally high sensitivity and specificity. In contrast, BLAB Parent Reports for L1 receptive ability failed to show significant correlations with the objective measures of receptive vocabulary. Conclusion: Subjective teacher ratings may be an effective method of screening bilingual preschoolers for language difficulty, thereby prompting referral to clinicians.

Cognition, brain atrophy, and cerebrospinal fluid biomarkers changes from preclinical to dementia stage of Alzheimer's disease and the influence of apolipoprotein e.

BACKGROUND: Knowledge of Alzheimer's disease (AD) manifestation in the pre-dementia stage facilitates the selection of appropriate measures for early detection and disease progression. OBJECTIVE: To examine the trajectories of cognitive performance, gray matter volume (GMV), and cerebrospinal fluid (CSF) biomarkers, together with the influence of apolipoprotein E (APOE) in subjects with amyloid-ß (Aß) deposits across the pre-clinical to dementia stages of AD. METHODS: 356 subjects were dichotomized into Aß+ and Aß- groups based on their CSF Aß1-42 level. We derived AD-related atrophic regions (AD-ROIs) using the voxel-based morphometry approach. We characterized the trajectories of cognitive scores, GMV at AD-ROIs, and CSF biomarkers from preclinical to disease stages in Aß+ subjects. The effect of APOE ε4 genotype on these trajectories was examined. RESULTS: Impairments in executive functioning/processing speed (EF/PS) and atrophy at the right supramarginal/inferior parietal gyrus were detected in cognitively normal Aß+ subjects. Together with the APOE ε4 carrier status, these measures showed potential to identify cognitively normal elderly with abnormal CSF Aß1-42 level in another independent cohort. Subsequently, impairment in memory, visuospatial, language, and attention as well as atrophy in the temporal lobe, thalamus, and mid-cingulate cortex were detectable in Aß+ mild cognitive impairment (MCI) subjects. In MCI and dementia Aß+ subjects, ε4 carriers had more severe atrophy of the medial temporal lobe and memory impairment but higher EF/PS compared to non-carriers. CONCLUSIONS: EF/PS decline and right parietal atrophy might act as non-invasive screening tests for abnormal amyloid deposition in cognitively normal elderly. APOE modulation on subsequent trajectories in cognition and atrophy should be taken into account when analyzing disease progression.