In 2022, ARI awarded more than $450,000 in grants to fund innovative research that holds realistic promise in impacting the lives of autistic people. At ARI we understand what it means to be different because ARI has always been unique. We have learned a lot over the past 55 years. We continue to focus on education while supporting research on genetics, neurology, co-occurring medical conditions, nutrition, sensory processing, severe and challenging behaviors, and adult and senior issues. Connecting investigators, professionals, parents, and those on the spectrum worldwide is essential for effective advocacy. 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.
More Research Studies
2022
miRNA as a potential mediator in maternal/fetal interaction in neurodevelopmental disorders
David Beversdorf, MD
University of Missouri
A significant increase in prenatal stressors is observed in late in pregnancies in children subsequently diagnosed with autism. In animal models, atypical social behavior is observed in offspring of rodent mothers exposed to stress during pregnancy, associated with epigenetic changes in the offspring brains. Prenatal stress in cases of clinical autism is associated with maternal stress susceptibility genes, and also associated with epigenetic changes in the maternal blood, overlapping with epigenetic changes observed in mice. We now wish to determine the mechanistic role of the micro-RNA (miRNA, small pieces of RNA with major regulatory effects) in the neurodevelopmental changes associated with prenatal stress. Our pilot data revealed the epigenetic changes in maternal blood in the prenatal stress mouse model, identifying the miRNA profile at the time of pregnancy. We now wish to determine whether the miRNA associated with prenatal stress, administered to pregnant mice, recapitulate behavioral (Aim 1), neurochemical (Aim 2), and other epigenetic effects (Aim 3) of prenatal stress exposure, to begin to understand the mechanism. This will allow better understanding of mediators of the effect of stress on development, identifying multiple points of intervention for a novel mechanism in the clinical setting for a subset of cases of autism.
Impact of environmental enrichment on the resolution of inflammation in a mouse model of Autism Spectrum Disorder
Paola Bonsi, PhD
Fondazione Santa Lucia
Neuroinflammation and aberrant activation of microglia, the brain immune cells, can drive derangements in the development and function of the brain, and are thought to be involved in the pathogenesis of diverse neurological conditions, among which Autism Spectrum Disorder (ASD). In recent years, neuroinflammation is emerging as a tightly regulated bidirectional process, involving both pro-inflammatory and pro-resolution (anti-inflammatory) signaling pathways. Dysregulation of these mechanisms may therefore underlie the persistence of a neuroinflammatory state, leading to pathological manifestations. Clinical, genetic, and experimental evidence indicates structural and functional alterations in a brain region called striatum in both individuals with autism and ASD mouse models. Our preliminary findings indicate that neuronal abnormalities in the striatum of an ASD mouse model showing autistic-like behaviors are accompanied by microglia-associated neuroinflammation and reduction of the pro-resolution activity.
The goal of our project is to find out whether boosting the physiological process of resolution of neuroinflammation is able to revert the neuronal and behavioral dysfunctions observed in the ASD mouse model. To this aim, we will utilize an innovative approach based on a non-pharmacological intervention providing social, cognitive and motor stimulation, defined “environmental enrichment.” The results of this study will provide crucial information on the role of alterations in the pro-inflammatory and pro-resolution pathways in ASD pathophysiology, and on the capability of the multimodal stimulation provided by environmental enrichment to revert such alterations and the ensuing neuronal and behavioral dysfunction.
Understanding Role of Peroxynitrite Signaling and Developing Therapeutic Intervention for Autism Spectrum Disorder
Adrien Eshraghi, MD, MSc, FACS
University of Miami Hearing Research and Communication Laboratory
Despite advances in medical field, there are still no effective medical treatments available for autism spectrum disorder (ASD) that can be attributed to the incomplete understanding about the pathophysiology of this neurological disorder. Intriguingly, we found the new avenues of developing effective therapeutic modalities for ASD from an entirely novel approach based on targeting protein tyrosine (Tyr) nitration by the oxidant peroxynitrite. The objective of this pilot study is to understand the role of peroxynitrite signaling in the pathophysiology of ASD. We will determine whether targeting peroxynitrite signaling will help in rescuing ASD associated behavior and social deficits in our preclinical animal model of ASD. This study will provide a novel catalogue of candidates that can be targeted to develop effective therapeutic interventions for ASD based on deep understanding regarding the role of peroxynitrite signaling in the molecular underpinnings of autism.
Placental Trophoblast Inclusions as Autism Risk Markers Among Preterm Infants
William Fifer, PhD, Principal Investigator
Morgan Firestein, PhD, Co-Investigator
Columbia University Irving Medical Center
The rising prevalence of autism spectrum disorder (ASD) and the effectiveness of early intervention places critical emphasis on the need to identify early emerging biological markers of risk. Trophoblast inclusions (TIs) in the placenta are histologically visible abnormalities within chorionic villi resulting from excessive cell proliferation of the inner cytotrophoblast layer. TIs are observed in only 2-8% of placentas from full-term uncomplicated pregnancies, however, a 3-fold increase in the number of TIs in placentas of children with ASD has been reported and TIs in placentas from children with familial risk for ASD were five times more prevalent. Moreover, TIs have been observed in 30-50% of placentas from preterm infants, a population at increased risk for ASD. Little is known about biological mechanisms underlying the association between preterm birth and increased risk for ASD and few tools reliably identify which infants are at greatest risk for ASD, potentially impeding earlier diagnosis and access to early intervention. The proposed research aims to determine if TIs are more prevalent in placentas of prematurely born infants determined to be at-risk for ASD at 18 months of age compared to prematurely born infants at low risk.
Zinc nutrition as key regulator of inflammatory gut-brain signaling in Autism
Andreas Grabrucker, PhD
University of Limerick
The microbiota-gut-brain axis and its role in healthy brain development and function have recently moved into the focus of research aiming at understanding the etiology of disorders of the Central Nervous System, including Autism Spectrum Disorders (ASDs). Increased inflammation due to a pathology in the gastrointestinal (GI) tract is considered a major contributor to abnormal gut-brain signaling. Accordingly, altered microbiota profiles, impaired intestinal barrier tightness, and the resulting activation of pro-inflammatory pathways have been reported in ASDs.
To better understand cause and consequence relationships, we will uncouple the effects of microbiota and inflammation on GI physiology, using 3D stem cell-derived intestinal organoids. Using these model systems, we can either induce bacterial components, or induce inflammation, or both. Moreover, we can investigate whether the presence of probiotic bacterial components or nutritional factors discussed in ASD prevent or normalize an observed pathology. For example, based on previous results we hypothesize that the pro-inflammatory processes in the GI tract are zinc-dependent. Our results will reveal whether zinc supplementation may be beneficial in conditions with compromised GI barrier tightness such as ASD and explore novel zinc supplements that we have characterized in the past.
Discovery of ASD related pathways in a novel preterm Rhesus macaque maternal immune activation model
Suhas Kallapur, MD
University of California Los Angeles
Epidemiological data demonstrate a strong association between intrauterine infection/inflammation (IUI) causing preterm birth (PTB) and neurodevelopmental/neurobehavioral defects during infancy. IUI, especially in the 3rd trimester, is an understudied maternal immune activation in ASD research but is important because recent data show an association between IUI and prematurity with ASD. We have modeled IUI in Rhesus macaques by giving intraamniotic (IA) live E. coli injection followed 24h later by antibiotics (E. coli + Abx) that results in neuroinflammation and preterm birth. Recently we demonstrated that maternal anti-IL1 (IL1 receptor antagonist, Anakinra) therapy significantly decreases IA E. coli + Abx-induced IUI. To better understand the link between neuroinflammation caused by IUI and ASD, we will comprehensively determine snRNA-seq changes in different brain regions of the fetal Rhesus macaque brain exposed to IA E. coli in the acute (24h-72h) phase of neuroinflammation. We will determine if maternal anti-inflammatory therapy with Anakinra can reverse neuroinflammation and reverse ASD related gene expression changes in different brain regions. This fetal brain transcriptomic study will reveal mechanistic insights in the pathogenesis of ASD.
Rescue of a neurodevelopmental disorder associated with ASD by induction of the heat shock response
Andrew Levy, PhD
Technion Israel Institute of Technology
Fever has been associated with the abatement of many of the social behavioral abnormalities seen in autism spectrum disorder. However, the lack of mechanistic studies exploring the mechanism for fever protection, due in large part to the lack of appropriate human disease models, has limited interest and use of this mode of therapy. A mutation in the IQSEC2 gene (A350V) was found to cause drug resistant epilepsy, autism spectrum disorder and intellectual disability. Fever in a child with this mutation has been associated with a cessation of seizures and improved social interactions [4]. Our working hypothesis, which we will test in this grant proposal, is that fever induces heat shock proteins which directly act to reduce activated Arf6. The specific aims of this proposal are based on published data underlying the key role of Arf6 activation in the pathophysiology of IQSEC2 mutations [8-10] and other ASD associated mutations [6] and our recent discovery that Arf6 activation is dramatically downregulated by the heat shock response. The long-term goals of this research are to determine the basic mechanism underlying the benefit from fever seen with A350V and other IQSEC2 mutations as well as in children with other ASD associated mutations, and to translate this into a treatment which will enhance social interactions, reduce the seizure burden and overall improve the quality of life of children afflicted with these disorders.
Characterizing Auditory Sensory Stability in Autism
Adam Naples, PhD
Yale University
Up to seventy percent of autistic people experience sensitivity to sounds. Autistic adults report that these symptoms worsen with stress and anxiety and can interfere with school, work, and other activities. However, despite the common report of these symptoms, there is no understanding of the mechanisms, nor are there effective ways to measure these symptoms.
Importantly, most measurement of these symptoms in autism relies on retrospective questionnaires. These measures require participants to “average” their symptoms over some time period in the past, possibly their entire lives. Such measures are well known to have “peak and end” biases in which people recall the most memorable and distressing experiences and the experiences that were most recent. This means that these questionnaires are not able to accurately capture the day-to-day lived experience of people with autism.
In this study we take the first step towards measuring the personal timing of auditory sensitivities, and their relationship with symptom report using an innovative approach. We measure auditory sensitivity using daily symptom self-reports and brief experimental auditory tasks delivered remotely over the internet. Participants will complete established self-report measures of sensory sensitivity and then will receive daily text-message or email reminders that will link to individualized questionnaires assessing sensory symptoms for that specific day. Additionally, participants will complete a brief tone detection task delivered via headphones on their computer or mobile device that will measure in-the-moment auditory perception.
The long-term goals of this study are to gain an understanding of the stability of auditory sensitivities to support subsequent mechanistic research. Currently there are no mechanistic biomarkers for auditory sensitivities in autism despite many successes in identifying group-level differences. Most research as assumed that auditory sensitivity symptoms are stable, over time, within an individual. However, if this assumption is invalid, then research that seeks to understand biological mechanisms will need to measure those symptoms at just the right time to find a brain-behavior linkage. This problem is exacerbated in autism because increased sensory sensitives are associated with avoidance of work and school. Consequently, autistic people may be less likely to participate in a research protocol on days when their symptoms are particularly distressing.
Autistic adults often report that these symptoms vary in intensity and frequency, however, there is no research that investigates if, how, or when these symptoms might vary. In this study, by determining how these sensitivities fluctuate over time, we gain a better understanding of the psychometric properties of auditory sensitivities, which provides insight into potential mechanisms. Furthermore, understanding the variability of symptom expression and auditory perception is critical information for developing and implementing successful in-person research studies.
Randomized placebo-controlled double-blind cross-over study of Coenzyme Q10, Vitamin E and polyvitamin B in a cohort of individuals with Autism Spectrum Disorder
Antonio M. Persico, M.D.
University of Modena and Reggio-Emilia (Modena, Italy)
Mitochondrial dysfunction and enhanced oxidative stress have been consistently detected in Autism Spectrum Disorder (ASD). Randomized controlled trials (RCTs) involving cocktails with multiple antioxidants have provided promising results, but cannot identify truly active compounds and maximize their efficacy. We recently published a retrospective chart review of 59 patients with neurodevelopmental disorders, demonstrating that approximately 60% of ASD cases and higher percentages of patients with Intellectual Disability display small-to-moderate improvements with rare and manageable side effects. Moreover, an exploratory RCT involving 31 patients with Phelan-McDermid syndrome (PMS) was recently completed (NCT04312152). This retrospective chart review and exploratory RCT allow us now to perform a precisely-designed, targeted RCT of a “metabolic support therapy” including Coenzyme Q10+Vit.E+Vit.B in ASD. Each patient will receive Coenzyme Q10+Vit.E+ polyvit. B for 6 months and placebo for 6 months separated by a one-week wash-out period, according to a double-blind cross-over design. Primary outcome measure of efficacy will be the CGI-I; secondary outcome measures of autism signs/symptoms, adaptive behaviors and parental quality of life will include VAS, VABS and WHOQOL, respectively. Tolerability and adverse events will be monitored. The study will involve 50 ASD patients, 25 children 2-7 y.o and 25 adolescents 9-17 y.o. Behavior, neuropsychological testing, and multiple oxidative stress parameters will be assessed at T0, T1 (6 mo) and T2 (12 mo). This study uses the most sensitive measures of clinical and biochemical change, and should be sufficiently powered to conclusively support or disconfirm the prescription of this metabolic support therapy to children with ASD.
Testing cannabinoid type 2 receptor (CB2R) as a potential therapeutic target in ASD: a pilot study on a mouse model of maternal immune activation
Anna Maria Tartaglione, PhD
Istituto Superiore di Sanità (ISS), Italy
Although Autism Spectrum Disorder (ASD) is identified by its social and communicative deficits, immune system impairments as well as signs of neuroinflammation have been frequently reported. The involvement of immune dysregulation in ASD is also supported by epidemiological evidence suggesting that maternal infection (and consequent maternal immune activation, MIA) increases the risk of ASD. In rodents MIA increases pro-inflammatory cytokines that cross the placenta causing long-lasting neuroinflammatory and behavioral responses in offspring, recapitulating hallmarks of ASD. However, mechanisms through which MIA leads to ASD-like phenotype are not yet fully understood. In this scenario, it is worthy of note that the endocannabinoid system (eCB) is a well-recognized modulator of both innate and adaptive immune responses, representing a bridge between the immune and central nervous systems. Interestingly, pharmacological activation of cannabinoid type 2 receptors (CB2R) recently gained attention, because of its ability to mitigate neuroinflammation in several neuropsychiatric disorders. Notwithstanding this evidence, the therapeutic potential of CB2R in ASD has not yet been investigated. To fill this gap, my research proposal aims to verify whether the CB2R stimulation (through JWH-133, a potent CB2R agonist) in prenatal and postnatal stages could prevent or revert the ASD-like behavioral phenotype and neuroinflammatory profile in mice prenatally exposed to MIA.
Home-based measurement of autonomic and endocrine system function and relations to sensory processing in children with and without autism
Jennifer Wagner, PhD
CUNY College of Staten Island
Autism spectrum disorder (ASD) is characterized by social-communicative challenges and restricted interests and repetitive behaviors (RRB), and research has suggested that difficulty regulating stress might underlie some of these associated characteristics. In line with this, studies have examined two key stress systems in ASD, the autonomic nervous system (ANS) and the hypothalamic-pituitary-adrenal axis (HPAA), and results show that social communication and RRB can be predicted by these systems. No known studies, however, have looked at the interacting patterns of ANS and HPAA activity as they align with sensory processing difficulties that are common in ASD and also vary widely in the general population. The current study will establish a novel protocol for home-based measurement of biomarkers related to the ANS and HPAA stress systems in children with and without ASD, utilizing a) pupillometry to collect markers of both parasympathetic and sympathetic autonomic function (through the constriction phase and the re-dilation phase of the pupil light reflex, respectively) and b) diurnal cortisol to examine HPAA axis integrity. These biomarkers will be examined alongside measures of autistic traits and sensory processing, and patterns of ANS and HPAA function will be used to explore variations in behavioral characteristics.
Is there a relationship between the gut mucosal-associated microbiome, intestinal neurotransmitters and behavior in individuals on the autism spectrum?
Harland Winter, MD
Massachusetts General Hospital
The relationship between behavioral disturbances and gastrointestinal (GI) dysfunction in individuals on the autism spectrum is well established, but the mechanism is not well understood. Intestinal microbiome imbalance (dysbiosis) has been described, but most studies have evaluated the microbiota in the stool. Clinical observations have reported that fecal microbiota transplants improved both behavioral and GI phenotypes in individuals with ASD. Additionally, gut microbiome modification through antibiotic (vancomycin) treatment resulted in transient improvement in measured behavior and communication. Although these findings implicate gut microbiome imbalance with behavioral alterations in ASD, exactly which signals are involved and how they communicate along the brain-gut axis are poorly understood. Mechanistic pathways of communication are starting to emerge, with accumulating evidence from clinical studies and animal models that GABAeric signaling is often inhibited in the brain in individuals with ASD. However, a major knowledge gap exists in our understanding of whether GABA signals are similarly affected in the intestine of ASD individuals, and, if so, whether the gut microbiome contributes to neurotransmitter imbalance and behavioral alterations.
The aim of this proposal is to test the hypothesis that a novel gut-brain axis signal is functionally coupled to specific microbiome activity in the colonic mucosa, and that behavioral phenotypes in ASD individuals correlate with intestinal neurotransmitter levels. We will test this hypothesis by:
- Characterizing the microbiome in paired colonic mucosa and stool of individuals who are on and not on the autism spectrum.
- Measuring neurotransmitter levels in paired mucosa and stool to determine if imbalance is related to uptake from microbial-produced GABA in the gut.
- Correlating the behavioral phenotype of all subjects with dysbiosis and neurotransmitter levels.
We expect this information will generate new knowledge about intestinal dysbiosis and the role of intestinal neurotransmitters in affecting behavior.