Molecular Autism最新文献

Background: Suicide has been reported as a leading cause of premature death in autistic populations. Additionally, risk of suicidality is often found to increase with age in the general population. Despite this, suicidality has seldom been explored in autistic populations in midlife and old age. This study investigates the self-reported prevalence of self-harm and suicidality in autistic people in midlife and old age compared to an age- and gender-ratio comparable non-autistic group.

Methods: In total, 388 participants (autistic n = 222, 44% men) aged 40-93 years (mean = 60.9 years) from the AgeWellAutism study completed questionnaires related to experiences of suicidal ideation, self-harming thoughts, deliberate self-harm, and suicidal self-harm. Group, gender and age differences were examined in chi-square and linear regression analyses.

Results: The autistic group reported significantly higher rates of suicidal ideation, self-harming thoughts, deliberate self-harm, and suicidal self-harm than the non-autistic comparison group. When considering gender differences in the autistic group (but not the non-autistic group due to limited sample size), autistic women reported significantly higher rates of suicidal ideation and suicidal self-harm compared to autistic men; no other gender differences were found. When considering age differences, autistic people in old age were more likely to have had thoughts of self-harm, to have deliberately self-harmed, and to have experienced suicidal self-harm than autistic people in midlife.

Limitations: The AgeWellAutism study is a cross-sectional convenience sample that relies on self-report. Survivor bias may also influence findings, as the study design would exclude those who have died by suicide, potentially leading to an underestimation of suicidality.

Conclusions: Autistic adults may be particularly susceptible to experiences of self-harm and suicidality in midlife and old age, particularly autistic women. Additionally, autistic people in old age were also more likely to experience suicidality (including recent experiences) than autistic people in midlife. These findings highlight the urgent need for targeted suicide prevention strategies and mental health interventions for autistic adults in midlife and old age, particularly autistic women and older people.

Background: Fragile X Syndrome (FXS) is the most prevalent inherited intellectual disability disorder linked to the X chromosome, and currently lacks an approved specific treatment. Preclinical and some clinical studies have suggested metformin may have therapeutic potential for FXS based on its mechanisms related to the disorder's pathophysiology.

Methods: We conducted a 6-month, randomized, double-blind, placebo-controlled trial at the Children's Hospital of Fudan University. Thirty-four participants aged 2-16 years with genetically confirmed FXS were randomized 1:1 to receive weight-adjusted metformin (250-1000 mg/day) or placebo. Primary outcomes were changes in Aberrant Behavior Checklist (ABC); secondary outcomes included Griffiths Development Scale-Chinese (GDS-C), Autism Diagnostic Observation Program Second Edition (ADOS-2), Children's Sleep Habits Questionnaire (CSHQ), Repetitive Behavior Scale-Revised Chinese version (RBS-R), and Clinical Global Impression (CGI).

Results: Among 34 randomized participants, 30 completed the trial (15 per group). Metformin demonstrated significant improvements in hyperactivity (ABC-Hyperactivity: -7.86 ± 6.97 vs. -0.80 ± 8.09, p = 0.016) and sleep disturbances (CSHQ-Total: -0.73 ± 5.14 vs. + 5.13 ± 6.85, p = 0.013), particularly bedtime resistance (p = 0.004). Total ABC score reductions favored metformin (-16.60 ± 15.31 vs. -4.00 ± 23.67) but did not reach significance (p = 0.095). No significant between-group differences were observed in cognitive, social, or repetitive behavior measures (GDS-C, ADOS-2, RBS-R). Adverse event rates were comparable, with IGF-1 reduced (6.7%, p = 1), transient appetite loss (13.3%, p = 0.483) and lactic acidosis (26.7%, p = 0.330) resolving spontaneously in metformin group.

Limitation: This study was constrained by its modest sample size (n = 30), and absence of objective neurophysiological measures. The 6-month duration precluded assessment of long-term therapeutic effects.

Conclusions: In this controlled trial, metformin did not significantly improve the primary outcome of ABC total score. However, significant improvements were observed in the hyperactivity subscale and key secondary outcomes, including sleep parameters, while maintaining a favorable safety profile. Although the primary endpoint was not met, these secondary findings support further investigation of metformin for targeted behavioral domains in individuals with FXS.

Trial registration: This trial was prospectively registered on ClinicalTrials.gov (Registration No. NCT05120505, first posted November 03, 2021). The full protocol can be accessed at https://register.

Clinicaltrials: gov/ .

Background: Despite high rates of autism spectrum disorder (ASD), understanding of pathophysiology is limited. The RAS-mitogen-activated protein kinase (RAS-MAPK) pathway plays a crucial role in ASD and is altered in children with Noonan syndrome (NS). Children with NS offer a unique model to disentangle genetic and neurological underpinnings of ASD.

Methods: This study aimed to examine functional brain network anatomy underlying social impairments in children with NS (n = 28, mean age = 8.24), and tested generalizability of models developed in a non-syndromic cohort enriched for ASD (Autism Brain Imaging Data Exchange (ABIDE), n = 352, mean age = 11.0). Connectome-based predictive modeling (CPM) was applied to fMRI data to predict the severity of autism symptoms, indexed by the Social Responsive Scale (SRS), in children with NS. Next, we tested if a model developed to predict autism symptoms in an autism-enriched sample of children without NS (ABIDE) could predict autism symptoms in children with NS.

Results: Predicted SRS scores were significantly associated with observed SRS scores in NS (r_s = 0.43, p = 0.011). Application of the predictive model generated in the autism-enriched cohort (ABIDE) significantly predicted observed SRS scores in NS (r_s = 0.46, p = 0.018). Predictive brain networks in both NS and the non-syndromic cohorts included subcortical-cerebellar networks and visual processing networks.

Limitations: The size of our NS cohort is small, given the rarity of NS. However, the significant cross-dataset comparison yielded in this study suggests that use of large publicly available datasets can be useful in contextualizing smaller and harder to collect datasets in rare genetic syndromes.

Conclusions: The presence of shared brain networks suggests converging patterns of functional connectivity underlying autism symptoms across diagnoses. These findings point to potential overlap between non-syndromic autism and NS and highlight the value of human genetic models for studying ASD. Future work investigating RAS-MAPK pathway dysregulation may further elucidate its contribution to autism-related brain function.

Background: Fragile X syndrome (FXS) is the most common inherited intellectual disability, caused by the loss of fragile X mental retardation protein (FMRP), which regulates neuronal signaling and plasticity. FXS patients and Fmr1 knockout (KO) mice exhibit sensory hypersensitivity, hyperarousal, and hippocampus-dependent learning deficits. Dysregulated metabotropic glutamate receptor (mGluR) and muscarinic acetylcholine receptor (mAChR) signaling, along with reduced kainate receptor (KAR) function, have been implicated in FXS pathophysiology. Activation of these signaling pathways induce gamma-frequency network oscillations hippocampal slices in vitro. However, their specific contribution to aberrant gamma oscillations in FXS remains unclear.

Methods: We recorded local field potential (LFP) gamma oscillations in vitro in hippocampal CA3 from wild-type (WT) and Fmr1 KO mice. Oscillations were induced pharmacologically using carbachol (CCh), the group I mGluR agonist dihydroxyphenylglycine (DHPG), or kainate (KA). In addition, we quantified synaptic protein expression of mAChR M1, mGluR1, mGluR5, GluK1, and GluK2-receptors involved in gamma oscillation generation under these conditions.

Results: Fmr1 KO slices exhibited increased integrated gamma power (20-80 Hz) in response to DHPG and CCh, suggesting higher network synchronization through mGluR and mAChR pathways. In contrast, KA-induced oscillations showed reduced synchrony and gamma peak power, indicating disrupted network coordination. Aberrant spiking activity during both CCh- and KA-induced oscillations further supports impaired temporal coordination in Fmr1 KO mice. These physiological changes were only partially reflected by altered expression of the corresponding receptor proteins.

Limitations: In the current study, we found aberrant gamma oscillation power in in vitro hippocampal slices of Fmr1 KO mice. It remains to be determined whether these oscillatory changes extend to pharmacologically induced gamma oscillations in cortical slice preparations in vitro.

Conclusions: Our findings demonstrate that hippocampal gamma oscillations are differentially affected by distinct neuromodulatory pathways in Fmr1 KO mice. Enhanced responsiveness to cholinergic and mGluR activation and reduced coherence of KA-induced rhythms suggest that multiple dysregulated mechanisms contribute to gamma oscillopathies in FXS.

Background: Neuronal connectivity is refined throughout development by the proliferation and pruning of axons in cerebral white matter, and progressive axon myelination that enables rapid communication across brain regions. Differences in connectivity have been observed in autism spectrum disorder (ASD), including changes in white matter volume and connectivity. In the prefrontal cortex, this includes imbalances between short- and long-ranging axons, consistent with a pattern of local hyperconnectivity, and long-range hypoconnectivity. Alterations in temporal lobe white matter development-critical for social behavior-may contribute to atypical neural connectivity.

Methods: We used electron microscopy to analyze 54 samples of temporal lobe white matter from 27 age-matched postmortem brains from males with ASD and neurotypical (NT) controls, ages 2-44 years. Defined regions of superficial (SWM) and deep (DWM) white matter were sampled from superior temporal (STG) and fusiform (FG) gyri. Axon density and myelin thickness were quantified, with axon size classified by inner diameter, to evaluate age-related differences between ASD and neurotypical brains.

Results: In neurotypical control brains, total axon density significantly decreases with age in both STG and FG SWM. Although ASD cases show a similar trend, the density of small axons in STG is significantly higher than in controls. However, FG SWM in ASD shows no significant change in small-diameter axon density with age in this region. In neurotypical brains, myelin thickness of large-diameter axons increases significantly with age in STG and FG SWM. In contrast, large-diameter axons in ASD display significantly thinner myelin sheaths than controls across both STG and FG regions.

Conclusions: The temporal lobe exhibits atypical patterns of white matter development in ASD. In neurotypical individuals, decreased axon density in SWM with age reflects effective neural pruning and refinement of local and short-range connectivity. In contrast, individuals with ASD maintain a high density of small-diameter axons in STG SWM, suggesting reduced pruning that results in local overconnectivity. Moreover, myelin thickness in SWM does not increase with age in ASD, implying reduced efficacy of neurotransmission. These alterations in white matter ultrastructure may contribute to the atypical connectivity and neural communication observed in ASD across the lifespan.

Objective: The dearth of tools to quantify and track growth in social communication ability has been a barrier to understanding and monitoring treatment outcomes for neurodevelopmental disorders. We undertook a multi-staged, multisite study to create the Developmental Assessment of Social Communication Ability (DASCA), a new measure explicitly developed as a clinical outcome assessment for monitoring change-both over the course of development and in response to treatment.

Methods: The DASCA is a caregiver-report instrument created using a mixed-methods approach. Qualitative components of this approach included focus groups and cognitive debriefing interviews. Quantitative components included dimensionality analysis, differential item functioning, and item response theory modeling. The item bank was iteratively refined to assess social communication skills that are typically acquired by early- to middle- childhood.

Results: The final DASCA item bank contains 184 items. Expressive language was a major factor in determining the appropriateness of some items for certain groups of children. Negligible differential item functioning, primarily by age, was observed for some items. However, impact analyses determined that this differential item functioning did not meaningfully impact overall scores.

Limitations: Given that sample size limitations prevented us from using separate samples for exploratory and confirmatory phases of modeling, it will be important to gather additional validity evidence in independent samples, especially as the current data were collected during the COVID-19 pandemic.

Conclusion: The DASCA holds promise as an outcome measure for assessing changes in social communication ability. Ongoing development efforts include creating a computer adaptive test administration to allow for serial assessments using different item sets to yield a consistent score that is sensitive to change.