Evaluation of the Diagnostic Stability of the Early Autism Spectrum Disorder Phenotype in the General Population Starting at 12 Months

Pierce, Karen; Gazestani, Vahid H.; Bacon, Elizabeth; Barnes, Cynthia Carter; Cha, Debra; Nalabolu, Srinivasa; Lopez, Linda; Moore, Adrienne; Pence-Stophaeros, Sunny; Courchesne, Eric

doi:10.1001/jamapediatrics.2019.0624

Cited by 246 publications

(201 citation statements)

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“…Autism spectrum disorder (ASD) is a neurodevelopmental disorder with an increasing global prevalence ranging from 42.6/10,000 in China to 1/58 in the United States 1,2 . ASD can be reliably diagnosed at 24 months or even as early as 18 months of age 3 , and is a life-long condition. Although the molecular and neural mechanisms underlying ASD remain largely unknown, a previous study suggested that ASD may result from alteration in brain development during early life, such as the excitatory-inhibitory (E-I) imbalance in the autistic brain can affect the sensory, memory and emotional systems 4 , indicating the necessity of early intervention.…”

Section: Introductionmentioning

confidence: 99%

Symptom improvement in children with autism spectrum disorder following bumetanide administration is associated with decreased GABA/glutamate ratios

et al. 2020

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Bumetanide has been reported to alter synaptic excitation-inhibition (E-I) balance by potentiating the action of γ-aminobutyric acid (GABA), thereby attenuating the severity of autism spectrum disorder (ASD) in animal models. However, clinical evidence of its efficacy in young patients with ASD is limited. This was investigated in the present clinical trial of 83 patients, randomised to the bumetanide group (bumetanide treatment, 0.5 mg twice daily) or the control group (no bumetanide treatment). Primary [Children Autism Rating Scale (CARS)], secondary [Clinical Global Impressions (CGI)], and exploratory [inhibitory (γ-aminobutyric acid, GABA) and excitatory (glutamate, Glx) neurotransmitter concentrations measured in the insular cortex (IC) and visual cortex (VC) by magnetic resonance spectroscopy (MRS)] outcome measures were evaluated at baseline and at the 3-month follow-up. Side effects were monitored throughout the treatment course. Compared with the control group, the bumetanide group showed significant reduction in symptom severity, as indicated by both total CARS score and number of items assigned a score ≥ 3. The improvement in clinical symptoms was confirmed by CGI. GABA/Glx ratio in both the IC and VC decreased more rapidly over the 3-month period in the bumetanide group than that in the control group. This decrease in the IC was associated with the symptom improvement in the bumetanide group. Our study confirmed the clinical efficacy of bumetanide on alleviating the core symptoms of ASD in young children and it is the first demonstration that the improvement is associated with reduction in GABA/Glx ratios. This study suggests that the GABA/Glx ratio measured by MRS may provide a neuroimaging biomarker for assessing treatment efficacy for bumetanide.

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Section: Introductionmentioning

confidence: 99%

Symptom improvement in children with autism spectrum disorder following bumetanide administration is associated with decreased GABA/glutamate ratios

et al. 2020

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“…To investigate the spatiotemporal activity of the DE-ASD network during brain development, we measured the magnitude of gene co-expression within the DE-ASD network at different neurodevelopmental time windows across brain regions. We found that the highest levels of co-expression of the DE-ASD network temporally coincided with peak neural proliferation in brain development (10)(11)(12)(13)(14)(15)(16)(17)(18)(19) post conception weeks 3,8 ), after which co-expression activity gradually decreased ( Fig. 2c; Fig.…”

Section: The Leukocyte-based Gene Network Captures Transcriptional Prmentioning

confidence: 88%

A perturbed gene network containing PI3K/AKT, RAS/ERK, WNT/β-catenin pathways in leukocytes is linked to ASD genetics and symptom severity

Gazestani

Pramparo

Nalabolu

et al. 2018

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Hundreds of genes are implicated in autism spectrum disorder (ASD) but the mechanisms through which they contribute to ASD pathophysiology remain elusive. Here, we analyzed leukocyte transcriptomics from 1-4 year-old male toddlers with ASD or typical development from the general population. We discovered a perturbed gene network that includes genes that are highly expressed during fetal brain development and which is dysregulated in hiPSC-derived neuron models of ASD. Highconfidence ASD risk genes emerge as upstream regulators of the network, and many risk genes may impact the network by modulating RAS/ERK, PI3K/AKT, and WNT/β-catenin signaling pathways. We found that the degree of dysregulation in this network correlated with the severity of ASD symptoms in the toddlers.These results demonstrate how the heterogeneous genetics of ASD may dysregulate a core network to influence brain development at prenatal and very early postnatal ages and, thereby, the severity of later ASD symptoms. that the network is mostly preserved at the co-expression level between ASD leukocytes and prenatal brain.Specifically, the direction of correlations (i.e., positive or negative) in the leukocyte transcriptome of subjects with ASD is mostly preserved in prenatal and early postnatal brain ( Fig. 2d). Importantly, this preservation of co-expression was significantly higher in the DE-ASD network than in the DE-TD network (p-value <10 -16 ; Fig. S6). rASD genes are associated with the DE-ASD networkWe next analyzed the DE-ASD network in the context of other studies to test the relevance of our DE-ASD network to ASD. Parikshak et al. previously reported gene co-expression modules associated with cortical laminae development during prenatal and early postnatal ages 11 . A subset of these modules show enrichment in rASD genes 11 . We examined the overlap of our leukocyte-derived network with all modules from Parikshak et al 11 . The DE-ASD network preferentially overlapped with rASD gene-enriched modules from that study ( Fig. 2e). This suggests that our DE-ASD network is functionally related to rASD genes during neocortical development. Our DE-ASD network also overlapped with the networks of rASD genes reported in other studies 7,9 , indicating the robustness of the results (Fig. 2e). Intriguingly, the prenatal brain co-expression network of high-confidence rASD genes was more similar to that of ASD leukocytes than TD leukocytes ( Fig. 2f), suggesting that neurodevelopmental transcriptional programs related to rASD genes might be more active in the leukocyte transcriptome of toddlers with ASD than in that of TD toddlers.With the observed overlap patterns, we next tested for enrichment of rASD genes in the DE-ASD network. For this analysis, we considered different rASD gene lists of different size and varying confidence levels (Methods). Surprisingly, this analysis demonstrated that rASD genes are not enriched in the DE-ASD network (p-value >0.19). The DE-ASD network is enriched for regulatory targets of rASD genesMany high confidence rASD...

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“…The prevalence of ASD has steadily risen to the current rate of 1 in 54 children in the U.S. (Maenner et al, 2020). In the past decade, the age for a reliable diagnosis of ASD has decreased to as early as 14-months with the recommended age for early diagnosis at 18-months (Hyman, Levy, & Myers, 2020;Pierce et al, 2019). Early diagnosis has led to an increased demand for developmental and behavioral early intervention.…”

Section: Introductionmentioning

confidence: 99%

Effects of a parent training using telehealth: Equity and access to early intervention for rural families

Rooks-Ellis

Howorth

Kunze³

et al. 2020

J Child Edu Soc

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Children living in geographically rural areas may have limited access to early, intensive evidence-based interventions suggesting children residing in these areas are less likely to experience positive outcomes than their urban-dwelling peers. Telehealth offers an option to rural families seeking early intervention by using communication technologies where providers are able to consult and deliver services in real-time over geographical distances. To our knowledge, no other study has examined the implementation of P-ESDM in rural natural environments within the framework of the state’s early intervention program. Using a multiple baseline design across participants, the current study investigated the effects of the parent-Early Start Denver Model implemented within a rural northeastern state’s existing IDEA Part C early intervention program. Parents demonstrated increased fidelity to intervention strategies and reported satisfaction with the program’s ease of implementation and observed child gains. Statistically significant pre-to post- change in children’s ASD symptomatology were reported for the domains of communication, social reciprocity and repetitive and restricted behaviors. Support for parent-mediated interventions, the importance of fidelity of implementation for sustainability of intervention strategies, and the need to explore telehealth as a viable service delivery option to improve developmental trajectories for toddlers with autism are discussed.

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Evaluation of the Diagnostic Stability of the Early Autism Spectrum Disorder Phenotype in the General Population Starting at 12 Months

Abstract: This study examines the diagnostic stability of autism spectrum disorder in a large cohort of toddlers starting at 12 months of age and compares this stability with that of toddlers with other disorders.

Cited by 246 publications

References 45 publications

Symptom improvement in children with autism spectrum disorder following bumetanide administration is associated with decreased GABA/glutamate ratios

Symptom improvement in children with autism spectrum disorder following bumetanide administration is associated with decreased GABA/glutamate ratios

A perturbed gene network containing PI3K/AKT, RAS/ERK, WNT/β-catenin pathways in leukocytes is linked to ASD genetics and symptom severity

Effects of a parent training using telehealth: Equity and access to early intervention for rural families

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