Abstract
Human and animal cross-sectional studies have shown that maternal levels of the inflammatory cytokine interleukin-6 (IL-6) may compromise brain phenotypes assessed at single time points. ...However, how maternal IL-6 associates with the trajectory of brain development remains unclear. We investigated whether maternal IL-6 levels during pregnancy relate to offspring amygdala volume development and anxiety-like behavior in Japanese macaques. Magnetic resonance imaging (MRI) was administered to 39 Japanese macaque offspring (Female: 18), providing at least one or more time points at 4, 11, 21, and 36 months of age with a behavioral assessment at 11 months of age. Increased maternal third trimester plasma IL-6 levels were associated with offspring’s smaller left amygdala volume at 4 months, but with more rapid amygdala growth from 4 to 36 months. Maternal IL-6 predicted offspring anxiety-like behavior at 11 months, which was mediated by reduced amygdala volumes in the model’s intercept (i.e., 4 months). The results increase our understanding of the role of maternal inflammation in the development of neurobehavioral disorders by detailing the associations of a commonly examined inflammatory indicator, IL-6, on amygdala volume growth over time, and anxiety-like behavior.
Non-clinical psychotic experiences (PEs) occur at over twice the rate of psychotic disorders along a continuum in the general population and increase risk for progression to diagnoseable disorders. ...Social isolation is a risk factor for psychotic disorders, although it is unclear if childhood social isolation increases risk for experience of non-clinical PEs later in life
.
Data come from the Gaz et Electricité (GAZEL) Youth Study (1991–1999) and the Trajectoires Épidémiologiques en Population (TEMPO) Study (2009–2011), a community-based prospective cohort study. Of 1,227 participants whose parents completed questionnaires (1999, participants aged 7–10 years) and who were followed-up (2011, participants aged 25–37 years), 333 had childhood social isolation and young adult PE data. Lifetime prevalence of PEs was 21%. Childhood social isolation was not associated with 0–1 PE in young adulthood (
p
= 0.74). However, childhood social isolation predicted the experience of ≥ 2 PEs in young adulthood, controlling for gender, age, and general health status (OR = 11.5, 95% CI = 2.5, 52.0,
p
= 0.002). Childhood social isolation predicts the risk of experiencing two or more lifetime PEs, which may increase the risk for subsequent progression to a diagnoseable psychotic disorder.
Measurement of language atypicalities in Autism Spectrum Disorder (ASD) is cumbersome and costly. Better language outcome measures are needed. Using language transcripts, we generated Automated ...Language Measures (ALMs) and tested their validity. 169 participants (96 ASD, 28 TD, 45 ADHD) ages 7 to 17 were evaluated with the Autism Diagnostic Observation Schedule. Transcripts of one task were analyzed to generate seven ALMs: mean length of utterance in morphemes, number of different word roots (NDWR), um proportion, content maze proportion, unintelligible proportion, c-units per minute, and repetition proportion. With the exception of repetition proportion (p Formula: see text), nonparametric ANOVAs showed significant group differences (pFormula: see text). The TD and ADHD groups did not differ from each other in post-hoc analyses. With the exception of NDWR, the ASD group showed significantly (pFormula: see text) lower scores than both comparison groups. The ALMs were correlated with standardized clinical and language evaluations of ASD. In age- and IQ-adjusted logistic regression analyses, four ALMs significantly predicted ASD status with satisfactory accuracy (67.9-75.5%). When ALMs were combined together, accuracy improved to 82.4%. These ALMs offer a promising approach for generating novel outcome measures.
The three members of the human neurexin gene family, neurexin 1 (NRXN1), neurexin 2 (NRXN2), and neurexin 3 (NRXN3), encode neuronal adhesion proteins that have important roles in synapse development ...and function. In autism spectrum disorder (ASD), as well as in other neurodevelopmental conditions, rare exonic copy-number variants and/or point mutations have been identified in the NRXN1 and NRXN2 loci. We present clinical characterization of four index cases who have been diagnosed with ASD and who possess rare inherited or de novo microdeletions at 14q24.3–31.1, a region that overlaps exons of the alpha and/or beta isoforms of NRXN3. NRXN3 deletions were found in one father with subclinical autism and in a carrier mother and father without formal ASD diagnoses, indicating issues of penetrance and expressivity at this locus. Notwithstanding these clinical complexities, this report on ASD-affected individuals who harbor NRXN3 exonic deletions advances the understanding of the genetic etiology of autism, further enabling molecular diagnoses.
Is the incidence of autistic disorder and other pervasive developmental disorders (PDDs) increasing? Recent epidemiological surveys of autistic disorder and other PDDs have heightened awareness of ...and concern about the prevalence of these disorders; however, differences in survey methodology, particularly changes in case definition and case identification over time, have made comparisons between surveys difficult to perform and interpret. Recent surveys suggest that the rate of all PDDs is about 60 per 10,000. The prevalence of autism today is estimated at 13 per 10,000, Asperger's disorder is approximately 3 per 10,000, and childhood disintegrative disorder is very rare at about 0.2 per 10,000. The assessment process, sample size, publication year, and geographic location of studies all have an effect on prevalence estimates. In addition, data from many of these surveys indicate correlates of autistic disorder and other PDDs with IQ, gender, and other medical disorders.
The GPHN gene codes for gephyrin, a key scaffolding protein in the neuronal postsynaptic membrane, responsible for the clustering and localization of glycine and GABA receptors at inhibitory ...synapses. Gephyrin has well-established functional links with several synaptic proteins that have been implicated in genetic risk for neurodevelopmental disorders such as autism spectrum disorder (ASD), schizophrenia and epilepsy including the neuroligins (NLGN2, NLGN4), the neurexins (NRXN1, NRXN2, NRXN3) and collybistin (ARHGEF9). Moreover, temporal lobe epilepsy has been linked to abnormally spliced GPHN mRNA lacking exons encoding the G-domain of the gephyrin protein, potentially arising due to cellular stress associated with epileptogenesis such as temperature and alkalosis. Here, we present clinical and genomic characterization of six unrelated subjects, with a range of neurodevelopmental diagnoses including ASD, schizophrenia or seizures, who possess rare de novo or inherited hemizygous microdeletions overlapping exons of GPHN at chromosome 14q23.3. The region of common overlap across the deletions encompasses exons 3-5, corresponding to the G-domain of the gephyrin protein. These findings, together with previous reports of homozygous GPHN mutations in connection with autosomal recessive molybdenum cofactor deficiency, will aid in clinical genetic interpretation of the GPHN mutation spectrum. Our data also add to the accumulating evidence implicating neuronal synaptic gene products as key molecular factors underlying the etiologies of a diverse range of neurodevelopmental conditions.
Autism spectrum disorders (ASD) are early onset neurodevelopmental syndromes typified by impairments in reciprocal social interaction and communication, accompanied by restricted and repetitive ...behaviors. While rare and especially de novo genetic variation are known to affect liability, whether common genetic polymorphism plays a substantial role is an open question and the relative contribution of genes and environment is contentious. It is probable that the relative contributions of rare and common variation, as well as environment, differs between ASD families having only a single affected individual (simplex) versus multiplex families who have two or more affected individuals.
By using quantitative genetics techniques and the contrast of ASD subjects to controls, we estimate what portion of liability can be explained by additive genetic effects, known as narrow-sense heritability. We evaluate relatives of ASD subjects using the same methods to evaluate the assumptions of the additive model and partition families by simplex/multiplex status to determine how heritability changes with status.
By analyzing common variation throughout the genome, we show that common genetic polymorphism exerts substantial additive genetic effects on ASD liability and that simplex/multiplex family status has an impact on the identified composition of that risk. As a fraction of the total variation in liability, the estimated narrow-sense heritability exceeds 60% for ASD individuals from multiplex families and is approximately 40% for simplex families. By analyzing parents, unaffected siblings and alleles not transmitted from parents to their affected children, we conclude that the data for simplex ASD families follow the expectation for additive models closely. The data from multiplex families deviate somewhat from an additive model, possibly due to parental assortative mating.
Our results, when viewed in the context of results from genome-wide association studies, demonstrate that a myriad of common variants of very small effect impacts ASD liability.
This article reviews 32 epidemiological studies of pervasive developmental disorders (PDDs) published between 1966-2001. The design and sample characteristics of the surveys are described. Surveys ...have suggested that the rate for all forms of PDDs are around 30/10,000, but more recent surveys suggest it might be as high as 60/10,000. (Contains references.) (Author/CR)
Editorial: The passage of time Fombonne, Eric
Journal of child psychology and psychiatry,
July 2019, 2019-07-00, 20190701, Letnik:
60, Številka:
7
Journal Article
Recenzirano
Odprti dostop
In this editorial, the author reflects on changes that occurred in the quality of research on developmental psychopathology over the last 35 years. This is illustrated in the increased quality of ...nine longitudinal studies that are included in the current issue of JCPP. Using approaches that capitalize on the passage of time, ranging from 28 days to 40 years across investigations, these studies employed multiple levels of analysis, used sophisticated statistical methods to control for confounding factors, included measurement at both the biological, cognitive, and behavioral levels, and collectively provided results that allow improved assessment of causality.
•Functional random forest identified transdiagnostic ASD and ADHD subtypes.•Subtypes are directly tied to ADHD symptoms, relevant to ASD and ADHD.•Neurocognitive subtypes do not map one to one with ...functional connectivity trends.•There may be multiple mechanistic “pathways” to observed phenotypes.
Those with autism spectrum disorder (ASD) and/or attention-deficit-hyperactivity disorder (ADHD) exhibit symptoms of hyperactivity and inattention, causing significant hardships for families and society. A potential mechanism involved in these conditions is atypical executive function (EF). Inconsistent findings highlight that EF features may be shared or distinct across ADHD and ASD. With ADHD and ASD each also being heterogeneous, we hypothesized that there may be nested subgroups across disorders with shared or unique underlying mechanisms.
Participants (N = 130) included adolescents aged 7–16 with ASD (n = 64) and ADHD (n = 66). Typically developing (TD) participants (n = 28) were included for a comparative secondary sub-group analysis. Parents completed the K-SADS and youth completed an extended battery of executive and other cognitive measures. A two stage hybrid machine learning tool called functional random forest (FRF) was applied as a classification approach and then subsequently to subgroup identification. We input 43 EF variables to the classification step, a supervised random forest procedure in which the features estimated either hyperactive or inattentive ADHD symptoms per model. The FRF then produced proximity matrices and identified optimal subgroups via the infomap algorithm (a type of community detection derived from graph theory). Resting state functional connectivity MRI (rs-fMRI) was used to evaluate the neurobiological validity of the resulting subgroups.
Both hyperactive (Mean absolute error (MAE) = 0.72, Null model MAE = 0.8826, (t(58) = −4.9, p < .001) and inattentive (MAE = 0.7, Null model MAE = 0.85, t(58) = −4.4, p < .001) symptoms were predicted better than chance by the EF features selected. Subgroup identification was robust (Hyperactive: Q = 0.2356, p < .001; Inattentive: Q = 0.2350, p < .001). Two subgroups representing severe and mild symptomology were identified for each symptom domain. Neuroimaging data revealed that the subgroups and TD participants significantly differed within and between multiple functional brain networks, but no consistent “severity” patterns of over or under connectivity were observed between subgroups and TD.
The FRF estimated hyperactive/inattentive symptoms and identified 2 distinct subgroups per model, revealing distinct neurocognitive profiles of Severe and Mild EF performance per model. Differences in functional connectivity between subgroups did not appear to follow a severity pattern based on symptom expression, suggesting a more complex mechanistic interaction that cannot be attributed to symptom presentation alone.
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