1. Adamou M, Jones SL, Wetherhill S. Predicting diagnostic outcome in adult autism spectrum disorder using the autism diagnostic observation schedule, second edition. BMC Psychiatry ;2021 (Jan 10) ;21(1):24.

BACKGROUND : The Autism Diagnostic Observation Schedule, Second Edition (ADOS-2) module four assessment for diagnosing autism spectrum disorder in adults has shown good sensitivity and specificity in research settings. METHOD : This study aimed to evaluate the predictive accuracy of the ADOS-2 module four by investigating the components of the assessment, in relation to diagnostic outcome in a clinical setting. Data from 88 service users referred to a Specialist Adult Autism Service was explored. RESULTS : ADOS-2 scores failed to predict the diagnostic outcome (overall sensitivity = 92%, specificity = 57%). Interestingly, scores from the ‘restricted interests’ component of the ADOS-2 have the potential to predict diagnostic outcome, despite this domain not been included in the scoring algorithm. CONCLUSIONS : Based on our findings, we recommend clinicians are cautious when interpreting results of the ADOS-2 assessment.

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2. Cárdenas-de-la-Parra A, Lewis JD, Fonov VS, Botteron KN, McKinstry RC, Gerig G, Pruett JR, Jr., Dager SR, Elison JT, Styner MA, Evans AC, Piven J, Collins DL. A voxel-wise assessment of growth differences in infants developing autism spectrum disorder. Neuroimage Clin ;2020 (Dec 29) ;29:102551.

Autism Spectrum Disorder (ASD) is a phenotypically and etiologically heterogeneous developmental disorder typically diagnosed around 4 years of age. The development of biomarkers to help in earlier, presymptomatic diagnosis could facilitate earlier identification and therefore earlier intervention and may lead to better outcomes, as well as providing information to help better understand the underlying mechanisms of ASD. In this study, magnetic resonance imaging (MRI) scans of infants at high familial risk, from the Infant Brain Imaging Study (IBIS), at 6, 12 and 24 months of age were included in a morphological analysis, fitting a mixed-effects model to Tensor Based Morphometry (TBM) results to obtain voxel-wise growth trajectories. Subjects were grouped by familial risk and clinical diagnosis at 2 years of age. Several regions, including the posterior cingulate gyrus, the cingulum, the fusiform gyrus, and the precentral gyrus, showed a significant effect for the interaction of group and age associated with ASD, either as an increased or a decreased growth rate of the cerebrum. In general, our results showed increased growth rate within white matter with decreased growth rate found mostly in grey matter. Overall, the regions showing increased growth rate were larger and more numerous than those with decreased growth rate. These results detail, at the voxel level, differences in brain growth trajectories in ASD during the first years of life, previously reported in terms of overall brain volume and surface area.

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3. Choi B, Shah P, Rowe ML, Nelson CA, Tager-Flusberg H. A Longitudinal Study of Parent Gestures, Infant Responsiveness, and Vocabulary Development in Infants at Risk for Autism Spectrum Disorder. J Autism Dev Disord ;2021 (Jan 8)

We investigated gestures that parents used with 12-, 18-, and 24-month-old infants at high or low risk for autism spectrum disorder (ASD ; high-risk diagnosed with ASD : n = 21 ; high-risk classified as no ASD : n = 34 ; low-risk classified as no ASD : n = 34). We also examined infant responses to parent gestures and assessed the extent to which parent gesture relates to vocabulary development. Parents of three groups gestured in similar frequencies and proportions. Infants, in turn, responded similarly to parent gestures regardless of the infant’s ASD risk and later diagnosis. Finally, parents who gestured more at 12 months had children with better vocabulary at 36 months than parents who gestured less. These findings highlight the importance of examining parent gestures when predicting language development.

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4. Del Giudice T, Dose C, Görtz-Dorten A, Steiner J, Bruning N, Bell H, Roland P, Walter D, Junghänel M, Döpfner M. Dimensions of Autistic Traits Rated by Parents of Children and Adolescents with Suspected Autism Spectrum Disorders. J Autism Dev Disord ;2021 (Jan 8)

To examine the factor structure of autism spectrum disorder (ASD) and the psychometric properties of the German Symptom Checklist for Autism Spectrum Disorders (SCL-ASD). Data were collected from 312 clinical referrals with suspected ASD (2-18 years). Confirmatory factor analyses and analyses of reliability, convergent and divergent validity were performed. A bifactor model with one general ASD factor and two specific factors (interaction-communication ; restricted, repetitive behaviors) provided an adequate data fit. Internal consistencies of the SCL-ASD subscales and the total scale were > .70. Correlations with measures of ASD traits were higher than correlations with measures of externalizing and internalizing symptoms. The results support a factor structure consistent with DSM-5/ICD-11 criteria. The SCL-ASD has sound psychometric properties.

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5. Fu Y, Zhang J, Li Y, Shi J, Zou Y, Guo H, Yao Z, Wang Y, Hu B. A novel pipeline leveraging surface-based features of small subcortical structures to classify individuals with autism spectrum disorder. Prog Neuropsychopharmacol Biol Psychiatry ;2021 (Jan 10) ;104:109989.

Autism spectrum disorder (ASD) is accompanied with widespread impairment in social-emotional functioning. Classification of ASD using sensitive morphological features derived from structural magnetic resonance imaging (MRI) of the brain may help us to better understand ASD-related mechanisms and improve related automatic diagnosis. Previous studies using T1 MRI scans in large heterogeneous ABIDE dataset with typical development (TD) controls reported poor classification accuracies (around 60%). This may because they only considered surface-based morphometry (SBM) as scalar estimates (such as cortical thickness and surface area) and ignored the neighboring intrinsic geometry information among features. In recent years, the shape-related SBM achieves great success in discovering the disease burden and progression of other brain diseases. However, when focusing on local geometry information, its high dimensionality requires careful treatment in its application to machine learning. To address the above challenges, we propose a novel pipeline for ASD classification, which mainly includes the generation of surface-based features, patch-based surface sparse coding and dictionary learning, Max-pooling and ensemble classifiers based on adaptive optimizers. The proposed pipeline may leverage the sensitivity of brain surface morphometry statistics and the efficiency of sparse coding and Max-pooling. By introducing only the surface features of bilateral hippocampus that derived from 364 male subjects with ASD and 381 age-matched TD males, this pipeline outperformed five recent MRI-based ASD classification studies with >80% accuracy in discriminating individuals with ASD from TD controls. Our results suggest shape-related SBM features may further boost the classification performance of MRI between ASD and TD.

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6. García-Domínguez I, Suárez-Pereira I, Santiago M, Pérez-Villegas EM, Bravo L, López-Martín C, Roca-Ceballos MA, García-Revilla J, Espinosa-Oliva AM, Rodríguez-Gómez JA, Joseph B, Berrocoso E, Armengol J, Venero JL, Ruiz R, de Pablos RM. Selective deletion of Caspase-3 gene in the dopaminergic system exhibits autistic-like behaviour. Prog Neuropsychopharmacol Biol Psychiatry ;2021 (Jan 10) ;104:110030.

Apoptotic caspases are thought to play critical roles in elimination of excessive and non-functional synapses and removal of extra cells during early developmental stages. Hence, an impairment of this process may thus constitute a basis for numerous neurological and psychiatric diseases. This view is especially relevant for dopamine due to its pleiotropic roles in motor control, motivation and reward processing. Here, we have analysed the effect of caspase-3 depletion on the development of catecholaminergic neurons and performed a wide array of neurochemical, ultrastructural and behavioural assays. To achieve this, we performed selective deletion of the Casp3 gene in tyrosine hydroxylase (TH)-expressing cells using Cre-loxP-mediated recombination. Histological evaluation of most relevant catecholaminergic nuclei revealed the ventral mesencephalon as the most affected region. Stereological analysis demonstrated an increase in the number of TH-positive neurons in both the substantia nigra and ventral tegmental area along with enlarged volume of the ventral midbrain. Analysis of main innervating tissues revealed a rather contrasting profile. In striatum, basal extracellular levels and potassium-evoked DA release were significantly reduced in mice lacking Casp3, a clear indication of dopaminergic hypofunction in dopaminergic innervating tissues. This view was sustained by analysis of TH-labelled dopaminergic terminals by confocal and electron microscopy. Remarkably, at a behavioural level, Casp3-deficient mice exhibited impaired social interaction, restrictive interests and repetitive stereotypies, which are considered the core symptoms of autism spectrum disorder (ASD). Our study revitalizes the potential involvement of dopaminergic transmission in ASD and provides an excellent model to get further insights in ASD pathogenesis.

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7. Kurosaki T, Imamachi N, Pröschel C, Mitsutomi S, Nagao R, Akimitsu N, Maquat LE. Loss of the fragile X syndrome protein FMRP results in misregulation of nonsense-mediated mRNA decay. Nat Cell Biol ;2021 (Jan) ;23(1):40-48.

Loss of the fragile X protein FMRP is a leading cause of intellectual disability and autism(1,2), but the underlying mechanism remains poorly understood. We report that FMRP deficiency results in hyperactivated nonsense-mediated mRNA decay (NMD)(3,4) in human SH-SY5Y neuroblastoma cells and fragile X syndrome (FXS) fibroblast-derived induced pluripotent stem cells (iPSCs). We examined the underlying mechanism and found that the key NMD factor UPF1 binds directly to FMRP, promoting FMRP binding to NMD targets. Our data indicate that FMRP acts as an NMD repressor. In the absence of FMRP, NMD targets are relieved from FMRP-mediated translational repression so that their half-lives are decreased and, for those NMD targets encoding NMD factors, increased translation produces abnormally high factor levels despite their hyperactivated NMD. Transcriptome-wide alterations caused by NMD hyperactivation have a role in the FXS phenotype. Consistent with this, small-molecule-mediated inhibition of hyperactivated NMD, which typifies iPSCs derived from patients with FXS, restores a number of neurodifferentiation markers, including those not deriving from NMD targets. Our mechanistic studies reveal that many molecular abnormalities in FMRP-deficient cells are attributable-either directly or indirectly-to misregulated NMD.

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8. Liu SH, Shi XJ, Fan FC, Cheng Y. Peripheral blood neurotrophic factor levels in children with autism spectrum disorder : a meta-analysis. Sci Rep ;2021 (Jan 8) ;11(1):15.

Increasing evidence suggests that abnormal regulation of neurotrophic factors is involved in the etiology and pathogenesis of Autism Spectrum Disorder (ASD). However, clinical data on neurotrophic factor levels in children with ASD were inconsistent. Therefore, we performed a systematic review of peripheral blood neurotrophic factors levels in children with ASD, and quantitatively summarized the clinical data of peripheral blood neurotrophic factors in ASD children and healthy controls. A systematic search of PubMed and Web of Science identified 31 studies with 2627 ASD children and 4418 healthy controls to be included in the meta-analysis. The results of random effect meta-analysis showed that the peripheral blood levels of brain-derived neurotrophic factor (Hedges’ g = 0.302 ; 95% CI = 0.014 to 0.591 ; P = 0.040) , nerve growth factor (Hedges’ g = 0.395 ; 95% CI = 0.104 to 0.686 ; P = 0.008) and vascular endothelial growth factor (VEGF) (Hedges’ g = 0.097 ; 95% CI = 0.018 to 0.175 ; P = 0.016) in children with ASD were significantly higher than that of healthy controls, whereas blood neurotrophin-3 (Hedges’ g = – 0.795 ; 95% CI = – 1.723 to 0.134 ; P = 0.093) and neurotrophin-4 (Hedges’ g = 0.182 ; 95% CI = – 0.285 to 0.650 ; P = 0.445) levels did not show significant differences between cases and controls. Taken together, these results clarified circulating neurotrophic factor profile in children with ASD, strengthening clinical evidence of neurotrophic factor aberrations in children with ASD.

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