The Autism Research Institute (ARI) conducts, sponsors, and supports research on the underlying causes of, and treatments for, Autism Spectrum Disorders (ASDs). In order to provide parents and professionals with an independent, unbiased assessment of causal and treatment efficacy issues, ARI seeks no financial support from government agencies or drug manufacturers.
We therefore rely on the generosity of donors so that we may continue to advance autism research. Our founder Dr. Bernard Rimland would often say, ‘Research that makes a difference!’ to remind us of the need to focus on what might be beneficial here and now for people with ASDs.
Assessing Novel Impacts of RASopathies on Cortical GABAergic Neurons
Daniel Vogt, Michigan State University
Autism spectrum disorder (ASD) may be caused by multiple factors, including environmental impacts and gene mutations, the latter with several hundred genes implicated. It has been difficult to study ASD due to the shear enormity of the factors at play and multitude of symptoms that manifest. However, there are several monogenetic syndromes with high rates of ASD that may be the low hanging fruit (one gene that leads to ASD symptoms) that could uncover which biological mechanisms are altered, and in turn, may be targeted, to alleviate ASD symptoms. The RASopathies are syndromes caused by mutations in genes regulating the RAS/MAPK pathway, which is associated with high rates of ASD. While much work has uncovered genetic causes of these syndromes, the molecular and cellular changes, and their contribution to ASD symptoms, are poorly understood. We deleted the RASopathy gene, Nf1, in GABAergic interneurons, and uncovered a drastic loss of a key GABAergic control gene and loss of a specific types of interneuron, i.e. those expressing parvalbumin (PV). Since GABAergic neurons are the primary driver of brain inhibition, this discovery may uncover some mechanisms underlying the neuropsychiatric changes in ASD. This proposal will be the first to assess the core GABAergic molecular program in RASopathy models with low to high rates of ASD diagnoses as well as correlate our findings with rates of ASD diagnoses. Moreover, PV+ neurons have been implicated in human ASD cases and in many animal gene models of ASD, suggesting that understanding how these cells are impacted could provide new inroads into ASD.
Corneal Confocal Microscopy: A Surrogate Marker for Neurodegeneration in Autism
Rayaz Malik, Weill Cornell Medicine, Qatar
Major challenges in managing people with Autistic Spectrum Disorder (ASD) include its heterogeneity, poor knowledge of disease trajectories and an inability to accurately identify the extent and progression of underlying neurodegeneration. Neuroimaging studies confirm altered neural connectivity and trajectories for normal brain development, but lack precision. Whilst the focus of these studies has been on central brain pathology, recent studies show altered tactile discrimination and allodynia on the face, mouth, hands and feet of subjects with autism, indicating defects in peripheral somatosensory neurons. Indeed, a reduction in lower limb intraepidermal nerve fibre density has been reported in children with autism. We have pioneered the technique of corneal confocal microscopy (CCM) to rapidly image corneal nerve fibres and established it as a biomarker for peripheral and central neurodegenerative disease. In our pilot study of eight children with ASD, we show a significant reduction in the corneal nerve fiber length (P<0.01) and branch density (P<0.01) compared to healthy controls. We propose to assess if CCM can act as a rapid and reliable non-invasive biomarker of neurodegeneration in people with ASD.
Examining the Impact of the Very Early Treatment of ASD Between 12-17 Months
Karen Pierce, University of California San Diego
Evidence is striking that autism begins in the womb, likely at around 20 weeks gestation. Yet, according to the CDC, most children do not receive a diagnosis and subsequent treatment until around age 4 years. Given the enormous plasticity of the human brain during the first years of life, the considerable time delay between the disorder’s fetal onset and eventual treatment is likely a missed opportunity. Leveraging our pediatrician network in San Diego and our Get SET Early ASD detection program that has been shown to detect ASD as young as 12 months we propose to examine the impact of very early, high intensity, treatment of ASD. Our “high intensity” treatment will combine pivotal response training with a social enhancement module, parent training, gaze contingent eye tracking, and sensory motor training for a total of about 24 hours per week for 6 months. A small sample of toddlers will start intensive treatment at very young ages (between 12-17 months) in comparison to toddlers that either started at an equally young age but did not receive intensive treatment, or started at a much later age. At baseline and outcome 6 months later, all toddlers will participate in a series of standardized tests that will measure symptom severity, social behavior, language, and cognition. Creating synergy with existing NIMH grants, toddlers will also participate in novel tests of visual social attention as determined via eye tracking and neural functional activation patterns as determined using sleep fMRI. To examine the impact of very early treatment, changes in standardized test scores, free play behaviors, eye tracking, and neural functional activation maps will be compared between 3 groups of toddlers: (1) Early Detected, High Intensity Treatment (N=4); (2) Early Detected, Community as Usual Treatment (N=4) and; (3) Late Detected, Community as Usual Treatment (N=4). Our overall goal is to collect pilot data aimed at testing the hypothesis that the timing and intensity of treatment engagement is the key to maximizing change in symptoms for toddlers with ASD.
Identifying Metabolic Differences During Pregnancies in Mothers of Children Later Diagnosed with ASD
James B. Adams, David Haas, Haiwei Gu, and Juergen Hahn, Arizona State University
Prenatal supplements with folate are known to reduce the risk of neurological birth defects, and also seem to significantly reduce the risk of a child developing ASD, especially if taken preconception or early in the pregnancy. Our recent research on mothers of children with autism (several years after they gave birth) suggests that they have many metabolic differences from mothers of typically-developing children, and suggests that certain nutritional supplements including folate could be important in improving their metabolism. So, we propose to investigate levels of those metabolites in blood samples that were stored from a pregnancy cohort of 10,000 women, and compare the metabolite levels during pregnancy in the mothers whose children developed ASD vs. those who developed typically. Our hope is that this study will lead to the discovery of other nutrients that may improve the mother’s metabolism and reduce the risk and/or severity of ASD in their children, as well as co-occurring symptoms including seizures, intellectual disability, gastrointestinal problems, and sensory sensitivities.
Single Session Intervention for Comorbid Internalizing Symptoms in ASD
Matthew Lerner, Stony Brook University
Teens with autism spectrum disorder (ASD) experience substantial internalizing (anxiety and depression) symptoms, as well as considerable social challenges, with direct effects on functional impairment and distress. Existing interventions for these symptoms are resource-intensive, with variable effects. Growth mindset single-session interventions (GM SSI) represent a promising, new, scalable approach to addressing these symptoms, which can be delivered via computer in just 30 minutes. GM SSIs have been shown to reduce internalizing symptoms in youth without ASD. This project is the first to examine a GM SSI in teens with ASD; it employs a randomized controlled design with a well-matched attention control (a supportive therapy [ST] SSI). This project will evaluate effects of GM SSI on internalizing symptoms and core social and executive functioning outcomes. Thirty youth with ASD will be randomly assigned to receive the GM SSI or ST SSI. They will complete a single assessment/intervention visit, with immediate pre-post assessment, then return after 3 months for follow-up. This approach allows for identification of whether GM SSIs can be effective for youth with ASD while controlling for nonspecific treatment factors, thereby enhancing the strength and interpretability of any obtained findings.
The Domino-Drosophila Ensemble for the Functional Validation of New ASD Genes
Alexandros Kanellopoulos, University of Lausanne, Switzerland
Autism Spectrum Disorders (ASDs) are characterized by significant limitations in both intellectual functioning and adaptive behavior. Despite substantially different clinical phenotypes and genetic contributions, there seems to be a convergence on common cellular pathways, which ultimately affect brain wiring, function and behavior. A large list of potential ASDs risk genes has been compiled through analysis of copy number variants (CNVs) or single-nucleotide polymorphisms (SNPs). In addition, whole-exome sequencing (WES) and whole-genome sequencing (WGS) lead to the identification of de novo, rare recessive heritable mutations. In contrast to recessive conditions, identification of dominant mutations for ASDs is more difficult, due to the abundance of benign heterozygous variants that create massive background noise.
In our innovative project we plan to identify and experimentally validate new genes for Autism. Specifically, our approach is based on a machine-learning algorithm which predicts with high confidence, which genes may harbor autosomal-dominant mutations, distinguishing the true ASDs risk genes from false-positive associations. We have currently extracted 141 de-novo mutations from a public database that possibly cause ASDs, and 7 of these are novel putative genes. The validation will be performed using the fruit fly Drosophila melanogaster, a valuable animal model for a medium-throughput screening.
Using Zebrafish to Help Identify Which Environmental Toxicants Could Increase Autism Risk
Edward Levin, Duke University
In the proposed project, we will use the zebrafish model to investigate the behavioral consequences of environmental toxicants affecting retinoic acid receptors (RARs) during early neural development. Zebrafish provide an efficient model which bridges the gap between high throughput cell based in-vitro models which can quickly screen many compounds on a basic level and complex but slow and expensive investigations of humans in epidemiological studies and rodents in experimental studies. We will study RAR acting compounds because RAR signaling plays a critical role in proper formation of the neural tube/plate. Disruption of RAR signaling such as with the anticonvulsant drug valproic acid (VPA) has been shown to increase risk of Autism. We anticipate that even modest disruptions in RAR signaling will not result in dramatic alteration in neural organization until a later stage of neurodevelopment when the brainstem nuclei project rostrally to help organize later more rostral neurodevelopment.
Then, the full phenotypic expression of the early neurotoxic injury may manifest in behavioral dysfunction. Here we propose that exposure to environmental toxicants affecting RAR signaling contribute to the increasing rates of Autism. We have found the zebrafish tests are sensitive to VPA and hypervitaminosis A induced impairments in social will be used to screen environmental compounds exhibiting RAR agonist activity which have been identified through mining recent Tox21/ToxCast high throughput screening data. Zebrafish offer a higher throughput and economic model system enabling analysis neurobehavioral consequences as affected by toxicants impacting RAR signaling during development thereby contributing to the risk of developmental neurobehavioral toxicity.