These current grants build on previous commitments by the National Alliance for Autism Research, or NAAR, and Cure Autism Now. From 1997-2004, NAAR funded $881,984 in grants on environmental factors (click here for details) while from 2000-2004 Cure Autism Now funded $748,041 in such research (click here for details). The combined funding commitment to date on autism environmental sciences is $8,079,117.
Topics of research include:
The direct role of toxicant, environmental factor or vaccine exposure
Studies which indirectly assess toxicant exposure, or pathways in which toxicants may act in the brain (for example, the immune system or the oxidative stress pathway)
Other areas of study of environmental factors:
- Molecular biology and toxicology using animal and in-vitro models
- Epidemiological studies in international territories, illustrating potential gene and environmental interactions
- Assessment of environmental factors which are not considered toxicants (for example, diet and prenatal hormone levels)
- The Interactive Autism Network (IAN)
Current Autism Speaks Grants on Environmental Factors (2005-2008)
Total Funding Commitment: $7,199,089
A. Studies in Which Toxicant, Environmental Factor or Vaccine Exposure Is Directly Examined (Direct Part of the Research Question):
PI: Adams (Mentor-based fellowship, 2005)
Early Markers of Autism and Social-Cognitive Processing in Infants Exposed to Valproic Acid During Prenatal Development ($54,000)
The use of drugs to control epilepsy (such as valproic acid) during pregnancy has been suggested to increase the risk for autism spectrum disorders in offspring. Thus far, data on autism risk has been based primarily on case reports, retrospective sample studies, and suggestions from animal research. This study will assess the developmental outcomes in a group of infants prenatally exposed to VPA, as well as a comparison group of infants matched by age, maternal age and demographic characteristics. It will also examine the effects of prenatal VPA exposure on motor, mental, and social-emotional development, as well as social-cognitive processing.
What this means for people with autism: This study will help clarify if there is indeed an increased risk of autism in children exposed to valproic acid in utero . Determination of environmental or pharmaceutical contributions to autism will contribute to development of better animal models and intervention strategies to prevent VPA associated cases of autism.
PI: Briscoe (Pilot Award, 2006)
Teratogen-Induced ASD and Brainstem Development. ($59,948)
While the etiology of autism and ASD is unknown, prenatal exposure to chemical teratogens including the antiseizure medications thalidomide and valproate are associated with increased incidences of ASD. Exposure to these agents is known to produce brainstem abnormalities which are reflected in individuals with autism. While the mechanism by which these defects are caused by these chemicals is being explored, the findings do raise the possibility that they may be similar to that which contributes to autism neuropathology. This project proposes to initiate a detailed analysis of the effect of thalidomide and valproate on different species of animals, including the rat, mouse, chick and zebrafish. The investigators will examine a panel of molecular markers – genes which will identify specific structures in the developing brainstem. The identification of chemical induced brain defects in these organisms will offer the opportunity for many follow up studies to determine the exact nature of the flaws and how they cause the symptoms of ASD.
What this means for people with autism: Because exposure to thalidomide and valproate has been associated with symptoms of autism spectrum disorder, an understanding of the specific biochemical and molecular effects of these teratogens during early brainstem development will help better identify disease mechanism. This information is likely to have far-reaching implications for understanding and diagnosing ASD and may aid the development of therapeutic interventions to treat or ameliorate ASD symptoms.
Ellen Carpenter, Ph.D.
University of California, Los Angeles
$60,000 for one year (2008)
Genetic and epigenetic interactions in a mouse model for autism
Autism likely results from a combination of genetic and environmental factors, and particular genetic variations may make an individual more sensitive to environmental factors. In this study, Dr. Carpenter and colleagues will examine the interaction between a specific gene and an environmental factor in the development of autistic-like behaviors in a mouse model. The gene to be examined in the present study, the reelin gene, is a candidate genetic factor for autism, and is important for the development of the cerebral cortex and cerebellum. Mice with reduced levels of expression of this gene have neurodevelopmental defects which result in behavioral abnormalities.
This research will examine the effects of an environmental factor hypothesized to be a risk factor for autism (organophosphate exposure during the prenatal period) on the development of autistic behaviors in mice which express low levels of the protein encoded by the reelin gene. It will also determine whether reduced reelin expression in combination with organophosphate exposure leads to changes in the anatomy of brain regions associated with these behaviors.
This research will determine whether the reelin gene and organophosphate exposure may be risk factors for autism, and whether genetic variation in the reelin gene increases developmental sensitivity to organophosphates.
PI: Croen (Augmentation and Bridge Award, 2006)
Augmentation of CA CADDRE Studies ($200,000)
Since 2001, the California Center for Autism and Developmental Disabilities Research and Epidemiology (CA CADDRE) has been one of the largest, most extensive datasets of information on children with autism living in California. CA CADDRE, funded by the Centers for Disease Control and Prevention, is run collaboratively by Dr. Croen from Kaiser Permanente's Division of Research and Drs. Grether and Windham from the Department of Health Services. The CA CADDRE center has also used Kaiser Permanente medical records to investigate autism risk factors during pregnancy and early childhood.
This grant will fund several new analyses of this rich dataset to examine risk factors for autism that have been speculated about in the literature. For example, Dr. Croen and her colleagues will investigate the risk of autism from:
- prenatal exposure to the immunization RhoGAM, which is given to women who deliver a Rh+ baby;
- maternal illnesses such as infections, inflammation and endocrine disorders;
- maternal hormone use, ultrasound exams and maternal use of the asthma drug terbutaline;
- maternal exposure to environmental chemicals, including airborne chemicals and workplace exposure.
PI: Freedman (Pilot Award, 2004)
Double Hit Hypothesis of Autism: Genetic Susceptibility and Environmental Exposure to Metals. ($120,000) (Received extension 2005 due to change in investigator to Ed Levin)
High level exposure to the heavy metals mercury and copper can lead to neuropsychological impairments in adults. Of concern, children are more susceptible to these cognitive impairments. While the levels at which exposure has led to dysfunction in motor and memory functions is considerably high, there are conditions under which an individual can not properly metabolize/detoxify metals, leading to a high bioburden compared to exposure level. Drs. Freedman and Levin will test whether a defect in metal metabolism (genetic) combined with exposure to copper or mercury (environmental) are causative factors in the development of autism like behaviors using an animal model. They will test the hypothesis that a disruption in normal metal metabolism and concomitant metal intoxication during development contributes to persistent cognitive and social impairment. Changes in cognitive and social behavior in response to exposure to copper or inorganic mercury will be examined in wild type mice and a transgenic strain in which a central component in metal metabolism, metallothionein, has been inactivated. The enzyme metallothionein is essential for removing heavy metals from the body, therefore this genetic manipulation may serve as a susceptibility factor to the deleterious effects of heavy metals such as mercury and copper.
What this means for people with autism: The information and improved mechanistic understanding obtained from the proposed studies will help define the roles of metal toxicants in the etiology of neurodevelopmental and neurobehavioral disorders. This information may be applied to the clinical intervention and possible prevention of metal-induced neurological disorders.
PI: Hall (CAN Pilot Project Grant, 2007)
Impact of Maternal Infection on Neurodevelopment - Structural and Functional Changes. ($119,760)
Although autism has a strong genetic component, early exposure to environmental insult may be a significant risk factor for the disorder. Exposure to known viruses during the first trimester of pregnancy has been connected to higher rates of autism. Animal modeling can be used to directly test if early exposure to immune challenges causes changes in brain structure, function and behavior that resemble changes seen in individuals with autism. Dr. Hall is interested in studying the behavior of mice that have been exposed to viral infection in-utero. Importantly, he will be assessing the neurological origins of these behaviors. Using recently available animal imaging methods he plans to assess the outcomes of maternal infection upon brain pathways key to autism, focusing especially on the dopamine and serotonin neurotransmitter systems. These methods offer the advantage over other techniques that the same animal can be studied across time. This provides the exciting opportunity to also study the effects of environmental manipulations on behavioral outcomes, and connect these results to the neurological changes seen throughout development. The overall objective of this study is to localize and quantify molecular events that occur in offspring as a result of maternal infection. This work holds promise for the development of new diagnostic tools and improvements in intervention.
PI: Hertz-Piccioto (Augmentation and Bridge Award, 2006)
Bridge Award to the CHARGE study ($25,000)
This study was awarded to Dr. Hertz-Piccioto to bridge NIEHS funding to her CHARGE study (Childhood Autism Risks from Genetics and the Environment). The CHARGE study has so far enrolled over 500 participants affected with autism, developmentally delayed, or not-affected. Her study examines toxicological exposures through biosampling as well as in depth interviews, monitors medical records as well as banks biosamples for genetic studies in order to examine gene-environment interactions.
PI: Hertz-Picciotto (CAN Pilot Project Award, 2006)
Polybrominated Diphenyl Ethers as a Potential Neurodevelopmental Toxicant ($118,012)
Both genetic and environmental factors contribute to autism in the majority of cases, yet few specific causes have been identified. In the search for relevant environmental exposures, chemicals affecting neurodevelopment are prime suspects. One such group of chemicals is the polybrominated diphenyl ether (PBDEs). These are flame-retardants used widely in consumer products, including plastic casings for television sets and computers, construction materials, carpeting and foam cushions. Levels of PBDEs are rapidly increasing in the environment and in human tissues, with body burdens in California among the highest worldwide. Of foremost concern is the neurodevelopmental toxicity of PBDEs demonstrated in animal studies. Prenatal exposures alter spontaneous behaviors, adversely affect learning and memory, and result in a lack of ability to habituate to a novel situation. PBDEs cross the placenta, accumulate in the fetus, and disrupt thyroid hormones, which are crucial for early brain, motor, language and sensory development. Thus, we will measure PBDEs in serum collected from children participating in a large epidemiologic study of autism. The CHARGE (Childhood Autism Risk from Genetics and the Environment) Study has enrolled over 400 subjects, including children with autism, children with developmental delay, and children from the general population. Over 300 of these children gave blood samples, from which we will select 90 (30 from each group) for measurement of PBDEs. This project will provide preliminary data to determine whether children with autism have higher concentrations of PBDEs than those from the general population or those with developmental delay but not autism.
PI: Keller (Interdisciplinary Award, 2005)
Comparative Analysis of Cerebellar Neuropathology in Human Autistic Patients and in Cerebellar Mouse Mutants ($292,024)
Neuroanatomical and neuroimaging studies in autism conducted by several research groups show faulty development of neural structures, particularly in a structure at the base of the brain called the cerebellum. The cerebellum is a particularly interesting research target because its structure and function has remained consistent throughout evolution. In addition, the development of the cerebellum takes place during late pregnancy and early postnatal life, which is a period that is believed to be critical for autism. Specifically, the size of the cerebellum is reported to be smaller in individuals with autism and the number of cells which direct messages to other brain areas, Purkinje cells, are shown to be reduced in number.
While the mechanism that affects Purkinje cell number and cerebellar size is not yet well described, preliminary data suggests that reelin, an autism candidate gene, interacts with gonadal sex hormones during cerebellar development. An interaction of abnormal reelin expression coupled with exposure to differing levels of testosterone during brain development may contribute to the reduced number of Purkinje cells in individuals with autism. This study will look for alterations of enzymes and receptors involved in gonadal steroid signaling in human brain tissue to determine the interaction between testosterone levels, reelin expression, and Purkinje cell development. The results of human brain tissue research will be followed by examining the effects of estrogen in a genetic strain of mouse named Reeler mice. Reeler mice lack the reelin protein which leads to a malformed cerebellum with disorganized Purkinje cells. By using this approach, the effects changes in gestational environment, including testosterone levels with genetic mutations on human pathology can be investigated in a multifaceted way.
What this means for people with autism: This study will investigate the interaction between genetic vulnerability and gonadal steroid hormones on Purkinje cell survival, migration, and/or differentiation, which would account for the biased sex ratio of autism. This hypothesis has not yet been tested and these researchers will examine the role of reelin, a candidate gene for autism, and 17beta-Estradiol, on mouse Purkinje cells. Dr. Keller's group will be linking animal models with human pathological studies in an interdisciplinary fashion and studying the possible protective role of estrogen on genetic susceptibility to autism spectrum disorders.
PI: Kornblum (Basic and Clinical Award, 2007)
Molecular and Environmental Influences on Autism Pathophysiology ($450,000)
Multiple studies have reported abnormal brain growth in people with autism, reflected by a larger head size early in development. This feature, called "macrocephaly" is determined in part by the number of times a cell divides as the brain matures. Using a cell culture technique, this study will examine genetic mutations of two genes associated with autism, PTEN and TSC on cell size and number. In addition to genetic influences, environmental factors could influence head size and cell division in the developing brain through production of reactive oxygen species (ROS). At low doses that are not toxic to neurons, these molecules have been known to produce changes in cell number. The current study will examine if ROS stimulates cell division through a similar pathway as PTEN and TSC mutations. The effects of prenatal exposure to low levels of ROS on cells with and without mutations of the PTEN gene will be assessed in parallel models to determine the interaction of the two on both brain size and cell number.
What this means for people with autism: Both genetic susceptibility and environmental factors have been linked to the cause of autism. This research will help scientists understand the basic neurobiology behind enlarged head size in people with autism, as well as isolate a specific molecular mechanism where environmental influences can interact with genetic factors to produce macrocephaly.
PI: McCaffrey (Pilot Award, 2005)
Disruption of Organization of the Cerebral Cortex by Retinoic Acid ($119,200)
Summary: Dysfunction of the cerebral cortex is likely to be a significant contributor to the pathogenesis of autism. One mechanism by which changes in cortical function may occur is by too much activity, leading to “overexcitation.” This may be caused by a dysregulation in systems that normally turn off neurons. In this study, Dr. McCaffery and associates will investigate the influence of retinoic acid, which inhibits the migration of specific neurons to the cortex and so would reduce the number of neurons that regulate brain activity. Retinoic acid has been suggested as one possible candidate of an environmental input that, in excess, may result in some features of autistic pathology. Fetal exposure to retinoic acid can occur through the use of a number of drugs that can influence the levels or potency of retinoic acid, including Accutane, alcohol, or valproate.
What this means for people with autism: Studying the effects of pharmaceutical agents and teratogens on brain development will help illustrate the mechanisms by which environmental factors may contribute to the neuropathology of autism.
PI: Newschaffer (Pilot Award, 2005)
Autism, Autoimmunity and the Environment ($120,000)
Summary: There is some evidence regarding an association between autism and autoimmunity, but the nature of this connection is still unclear. At the same time, given apparent upsurges in autism prevalence, interest into environmental risk factors continues to build. Because autism pathology likely begins early in development, the prenatal period is a critical time window for exposures to environmental risk factors. This study will look at two potentially related factors contributing to the fetal environment: maternal antibody levels and chemical exposures during pregnancy. The results of this research will add to the understanding of immunologic and environmental risk factors in autism.
What this means for people with autism: A reliable biomarker to enhance diagnosis of autism has not yet been well characterized or established. This study will explore autoantibodies as potential biomarkers of autism risk and will link biomarker data with ecologic data on environmental exposures.
PI: Newschaffer (Pilot Award, 2005)
Autism risk and Exposures/Biomarkers Measured During the pre-, peri-, and neonatal periods: a Baby Sibs Pilot Investigation ($120,000)
Given the strong evidence supporting the early origins of ASD, exposure and biomarker data collected during the pre-, peri- and neonatal time periods could be more strongly associated with ASD risk because they are measured during an etiologically more significant time period than those collected later in life. Also, although it is possible to collect interview data on pre-, peri- and neonatal exposures retrospectively, prospective collection offers substantive advantages in reducing error and limiting recall bias.
Collection of biomarker and exposure data in a high-risk cohort offers some distinct advantages over collecting these data in a population-based cohort. Most obvious is that, in a high-risk cohort, informative analyses can be completed with a relatively smaller sample size because clinical events are more common and there is greater variation in subclinical (continuously measured) endpoints. A second advantage of a high-risk cohort is compliance. Motivation to sustain study participation in the high-risk cohort would likely be higher on average then in a population-based cohort (although compliance and sample collection logistics are still a major challenge in this study design). Finally, studying a genetically susceptible population may allow for observation of associations between biomarkers and/or risk factors and ASD that would be more difficult to detect in a population-based sample.
What this means for people with autism: This investigation will demonstrate the feasibility of assembling and retaining a study population to determine if a larger study is possible. The pilot effort will also focus on data collection areas anticipated to present particular challenges – for example: the collection of biosamples during the labor and delivery, post-partum, and early neonatal periods. Finally, the pilot investigation will provide some data on the distribution of exposure and biomarker values observed during the pre-natal period, critical for brain development.
PI: Noble (CAN Pilot Project Grant, 2007)
Cellular, Physiological and Molecular Mechanisms Underlying Alterations in CNS Development Caused by Exposure to Clinically-Relevant Levels of Mercury-Containing Compounds ($120,000)
Dr. Noble's research aims to understand the mechanisms by which genetic factors and environmental insults combine to disrupt normal brain development and cause complex neurological syndromes such as autism spectrum disorders (ASD). His laboratory is interested in understanding how identical insults can have different outcomes in different individuals. The goal of the research is to provide a mechanistic understanding of vulnerability to physiological stressors implicated in ASD. Previous work from the Noble lab has shown that the state of oxidative stress of individual cells ("redox state") controls how they react to various environmental agents. The importance of redox states in controlling multiple cell functions is of potential interest given the observations that some data suggests individuals with ASD show signs of being in a more oxidized status. This condition may make them more vulnerable to physiological stressors. These studies will focus on thimerosal and methyl mercury in order to understand the cellular basis for vulnerability to these toxicants, and are designed to provide general principles relevant to understanding how any toxicant impinges on normal cell development. As a part of the proposed research, Dr. Noble aims to uncover approaches to identifying oxidative stress that could provide the basis for early identification of children at particular risk of damage from environmental toxins. They will further apply this knowledge to the identification of a means to protect such individuals by studying the efficacy of anti-oxidant compounds in protecting against the cellular effects of thimerosal and methyl mercury.
PI: Wagner (Pilot Award, 2005)
Animal Model of autism Using Engrailed2 Knockout Mice. ($98,880)
Autism is a neurobiological disorder with primary symptoms include impaired communication and social interaction with restricted or repetitive motor movements. Dr. Wagner and his colleagues have developed a model that examines the neurobehavioral development of mice in three core areas: motor, cognitive, and social. As the EN2 gene has been shown to be associated with autism, Dr. Wagner's lab will examine behavioral development in a mouse model where this gene is not expressed. Furthermore, the effects of two environmental toxicants, VPA and DEHP will be examined to determine if this gene confers susceptibility to environmental exposures. He predicts that disruption of the En2 gene will alter the developmental path of the brain and lead to widespread behavioral changes that may be made worse in the presence of these toxicants.
What this means for people with autism: These studies may help clarify the genetic, neurobiological and environmental influences in autism. Finding genes involved in autism susceptibility and learning how they contribute to disease development will provide information that could lead to more effective treatments and interventions.
B. Other Studies Which Indirectly Examine Toxicant Exposure/Immune Function:
PI: Ashwood (CAN Pilot Project Award, 2006)
Immunological Phenotyping in Autism: A Screen for Potential Early Biomarkers of Activation ($120,000)
It is thought that the interaction of genetic susceptibility and exposure to nongenetic influences during critical periods of neurodevelopment plays a part in the development of autism. Virtually the entire research literature on autism emphasizes the multiple facets of this disorder. Taken together, these data indicate that ASD is, in reality, a group of disorders that share a common behavioral profile. To make progress in identifying the causes of these disorders it will be essential to develop diagnostic markers that will lead to unequivocal differentiation of the various phenotypes. We aim to demonstrate the presence of distinct immune phenotypes in ASD based on the level of activation of their immune response. We will identify and characterize the immune response in ASD by comparing the activation status and function of lymphocyte cell populations and their cytokine/chemokine profiles, firstly in peripheral blood and secondly in isolated cell cultures that receive immunological challenge. Immunological findings will be correlated with behavioral and biomedical factors to examine the relationship between the immune responses and clinical characteristics of autism. By elucidating the medical and biological correlates of autism, we hope to contribute to a clearer understanding of the early biological processes underlying this increasingly common disorder. A better understanding of the underlying biology may contribute to earlier identification and the development of more individual-based treatment regimens.
PI: Boulanger (Mentor-based Fellowship, 2006)
Modulation of Glutamate Receptor Trafficking in Autism: Role of MHC class I ($84,000)
There is growing evidence of an imbalance in neuronal signaling in the brains of some individuals with autism. The neurotransmitter glutamate is an important chemical that "turns on" neurons. Direct measures of glutamate neurotransmission have been used to measure proper neuronal signaling in animal models. Recent studies have linked the ability of neurons to respond to the neurochemical glutamate to the changes in immune response. Because maternal immune challenge during pregnancy may be a risk factor for autism in children, this raises the possibility that maternal immune challenge may alter glutamatergic neurotransmission. This is may be accomplished through modification of MHC class I molecules (major histocompatibility complex class I) in the developing fetal brain. MHC-I molecules are an essential part of the immune response which are now known to be expressed in the brain and modulate neuronal function.
Using a mouse model, Drs. Boulanger and Fourgeaud will test whether changes in MHC class I in the developing brain effects glutamate receptors, and whether these changes can be induced in the fetal brain by maternal immune challenge. Together with the projects mentored by Dr. McAllister and Dr. Patterson, the role of alterations in immune function on brain development and later behavioral function will be better understood.
What this means for people with autism: These studies could also provide a mechanistic link between maternal immune challenge, a significant environmental risk factor for autism, and glutamatergic dysfunction, a hallmark symptom of this disorder. Furthermore, the results of these studies may suggest new, immune-based strategies for the diagnosis, treatment, and prevention of autism.
PI: Boulanger (CAN Pilot Project Award, 2006)
Immune Genes and Abnormal Brain Development in Autism ($120,000)
In this study Dr. Boulanger outlines the connections between autism and immunological challenges. She will study how a variety of material infections, such as influenza, may affect the development and behavior of the fetus, even when the fetus shows no signs of direct infection itself. The fetal impact appears to be the result of a relatively nonspecific aspect of the maternal immune response, but is reflected in altered cytokines in the fetal brain. This study will use mouse models and autistic children to explore whether the expression of immune genes is altered in the autistic brain, perhaps highlighting the potential for immune-based diagnostics, treatment and prevention.
PI: Chauhan (Pilot Award, 2007)
Oxidative Stress and Immune Response in Autism ($119,974)
Dr. Chauhan and colleagues at the IBR will investigate biochemical changes associated with autism, particularly as they relate to markers of oxidative stress. Oxidative stress is a process that occurs when the generation of free radicals in the cell during normal metabolic processes overwhelms the normal defense mechanisms and leads to damage or death of cells in tissues essential to normal function. Oxidative stress has been associated with neurodegenerative diseases and may be linked to an abnormal immune response. This project will examine blood of children affected with autism and their non-affected siblings to determine various markers of oxidative stress, the inflammatory response and the function of the immune system. In addition to diagnostic assessment, the symptom severity will be established to better understand the influence of the oxidative stress and immune responses in subgroups of children with autism spectrum disorders.
What this means for people with autism: This study will allow the investigators to measure a wide array of markers associated with oxidative stress, thereby providing a better understanding of the mechanism by which oxidative stress may occur in individuals with autism. Isolation of a particular biomarker in a subgroup of children with autism will lead to better treatments and potentially improved diagnostic assessments.
Lisa Croen, Ph.D.
Kaiser Permanente Division of Research
$120,000 for 2 years (2008)
Early Biologic Markers for Autism
The prenatal period is a crucial period of brain development, and therefore the maternal environment can have an impact on fetal neurodevelopment. In particular, proteins of the maternal immune system during pregnancy may be able to affect the development of the fetal brain, as these proteins can cross the placenta and enter fetal tissues. Preliminary results have provided evidence that elevated levels of certain immune system proteins in the blood of pregnant women may be associated with an increased risk of autism in their children. During mid-pregnancy, these researchers found elevated levels of specific cytokines (proteins which attract immune cells to sites of infection), and the presence of autoantibodies, proteins which can recognize and bind to cells and proteins in the fetus. Maternal cytokines and autoantiodies could affect fetal brain development by binding and signaling to cells and proteins in the fetal brain, or they could affect the immune system of the fetus.
These researchers will extend their preliminary data by conducting a large controlled study on the association between levels of autoantibodies and cytokines in maternal blood samples during mid-pregnancy with the associated risks of autism and mental retardation in the offspring. 1200 mother-child pairs will be included in this study, as well as 200 siblings of autistic and mentally retarded children. These data will determine whether inappropriate activation of the immune system during pregnancy is associated with an increased risk of neurodevelopmental problems.
The results from this study should contribute to our understanding of the impact of the maternal environment on fetal development, and its contribution to autism. It may also provide new, early tests for an increased risk of autism. (Co-sponsor: The Higgins Family Charitable Foundation)
PI: Deth (CAN Pilot Project Award, 2006)
Glutathione-dependent Synthesis of Methylcobalamin: A Target for Neurodevelopmental Toxins ($117,880)
While the exact cause of autism is not yet known, research during the past several years has focused on the possibility that many cases of autism result from exposure to the ethylmercury-containing vaccine preservative thimerosal. A subgroup of exposed individuals may be less able to detoxify and eliminate heavy metals, placing them at higher risk. Previous work from our lab has shown that thimerosal and other heavy metals potently inhibit an enzyme that uses vitamin B12, and that this inhibition could lead to developmental disorders like autism. Thimerosal interferes with the process that converts dietary B12 to its active form, known as methylB12. MethylB12 has proven to be quite helpful in treating autism, which reinforces the idea that impaired methyl B12 synthesis may be an important contributing cause. Thus this project will investigate the biochemical pathway that makes methylB12 and will elucidate the mechanism by which thimerosal causes its inhibition. It will also compare the thimerosal susceptibility of this pathway in cells from siblings who did or did not develop autism. Preliminary results suggest that the autistic children's cells show greater sensitivity. Results from this study will help to clarify what causes autism and what makes one child more likely to develop autism than another.
PI: Holtzman (CAN Pilot Award, 2007)
Oxidative Phosphorylation in Cells from Autistic Individuals Compared to Non-Autistic Siblings ($120,000)
This study analyzes whether metabolic abnormalities contribute directly to the pathogenesis of autism. Using patient cell lines, the project is designed to identify any abnormalities in mitochondria and the generation of ATP, the chemical form of energy. If successful, these results will lead directly to studies of the genetic mutations or toxic reactions important in the development of autism.
PI: Jonakait (CAN Pilot Project Award, 2006)
Microglial Regulation of Cholinergic Development in the Basal Forebrain ($112,778)
While the neurobiological basis for autism remains poorly understood, neuropathological studies have detected structural abnormalities in certain brain regions suggesting that disruption of normal brain development may play a role in the disorder. Our work highlights one of those abnormal brain regions, the so-called cholinergic basal forebrain, that innervates important brain areas serving cognitive function. Autistic children have too many neurons in this region, but how such changes might occur in development has not been explained. Increasing evidence also suggests that fetal exposure to infectious agents or toxins with associated inflammation may play a role in the development of autism. Such infection or toxicity can extend to the embryonic brain where local inflammation might prove detrimental to the developing brain. Our own work performed on cultured rodent cells suggests that abnormal embryonic brain inflammation during development leads directly to abnormal neurodevelopmental outcomes. Specifically, it leads to the excess production of cholinergic neurons in the basal forebrain. Thus, we have shown directly that brain inflammation has important neurodevelopmental consequences. Our proposal seeks to extend those studies by investigating in vivo whether maternal infection will lead to a similar excess of cholinergic neurons in the fetal brain. We will also seek to determine whether several known inflammatory signals will act similarly in culture and what developmental mechanisms they might use to create excess numbers of these neurons. Finally, we hope to begin to identify the specific molecules that cause the basal forebrain to develop abnormally.
PI: Kawikova (Pilot Award, 2006)
Does Autoimmunity play a Role in the Pathogenesis of Autism ($120,000)
Many neuropathological studies in autism have reported a reduction in numbers of cells in the brain in areas which control motor coordination and cognitive functioning. While the mechanism of this loss in cell number is unknown, a recent study demonstrated the presence of inflammation in the same brain areas. This suggests that an autoimmune process may play a role in the neuronal loss observed in autism. Autoimmunity occurs when the immune system not only protects the body against infectious microorganisms, but mounts an immune response against one's own tissue. This experiment will investigate whether the mechanisms which regulate autoimmunity are inadequate in children with autism and whether this is accompanied by signs of immune system activation. Measures of immune function will also be coupled with diagnostic instruments to shed light on whether changes in immune system activation is related to the severity of autism symptoms which is different from individual to individual.
PI: Le Belle (CAN Young Investigator Award 2006)
Molecular and Environmental Influences on Autism Pathophysiology ($80,000)
The incidence of macrocephaly (enlarged head) in the population of autistic patients is considerably higher than in control populations and indicates that this may contribute to the development of ASD. We are interested in what genetic and environmental changes underlie the development of macrocephaly and autism. Mutations in PTEN can be found in some autistic patients with macrocephaly. We have a mouse model of macrocephaly in which the gene PTEN has been deleted, resulting in the abnormal growth of brain cells, producing animals with large heads. We have recently shown that PTEN has a role in the ability of normal brain stem cells to self-renew, proliferate, and grow. We will use a relatively new technology in the study of gene expression in the brain, called microarray, to identify genes that are changed in our macrocephalic PTEN mutant mice. These experiments may identify genes and gene networks that contribute to ASD. We will also study how PTEN activity is affected by environmental factors. One such factor is oxidative stress. Oxidative stress is a general term used to describe oxidative damage to a cell, tissue, or organ, caused by reactive oxygen species. Most reactive oxygen species come from the internal sources as byproducts of normal cellular metabolism, such as energy generation from mitochondria. External sources include exposure to cigarette smoke, environmental pollutants such as emission from automobiles and industries, consumption of alcohol in excess, asbestos, exposure to ionizing radiation, and bacterial, fungal or viral infections. We and others have found that low levels of oxidative stress can enhance the self-renewal and proliferation of brain stem cells when grown in a culture dish, and this also results in decreased amounts of PTEN gene expression. We propose to look further at this potential mechanism by over-expressing pro-oxidant genes and disrupting anti-oxidant genes in cultured cells and in developing mouse embryos to determine if oxidative stress is a key environmental factor in the development of ASD with macrocephaly.
PI: Lipkin (CAN Pilot Project Award, 2006)
Histologic, Microbiological and Molecular Analyses of Bowel Disease in ASDs ($120,000)
Debilitating gastrointestinal (GI) dysfunction is described in some autistic children, possibly at higher frequency in individuals with a regressive phenotype. Its cause is unknown; however, some studies have implicated inflammation or infection. The significance of gastrointestinal dysfunction for brain dysfunction is controversial; some investigators have proposed that differences in GI microflora induce inflammation, influence permeability of the GI tract, or release novel neuroactive peptides that have remote effects in brain. Our project will use sensitive new assays for gene expression, microbiology and immunology to survey GI tract biopsies and blood from two groups of children: one group with GI dysfunction and autism, and one group with GI dysfunction but no neurological disturbance. The implication of an infectious agent (or agents) as factors (or cofactors) in autism or associated GI comorbidity could lead to new strategies for prophylaxis or therapeutic intervention. Discovery of distinct profiles of gene expression in GI tract or of soluble factors in peripheral blood may provide insights into pathogenesis; inform genetic analyses; and facilitate management by providing therapeutic targets and objective criteria for diagnosis and treatment response.
PI: McAllister (Mentor-based Fellowship, 2006)
The role of MHC class I molecules in synapse formation: possible implications for the pathogenesis of autism ($78,000)
Although there is a strong genetic component to autism and autism spectrum disorder, there are non-genetic causal factors. Maternal viral infection has been put forward as one such factor. During an infection, the immune system releases molecules called cytokines which then trigger an increase in MHC-I molecules. Dr MacAllister's team has previously shown that altered MHC-I levels can affect the brain by reducing the ability of neurons to form synapses and modifying existing connections. Therefore, it is possible that modifications of immune function may alter normal brain development and possibly produce symptoms of ASD.
This new research will investigate the specific role of cytokines on MHC-I expression and how these changes affect neuronal development. This will be done by measuring MHC-I levels after administration of cytokines as well as examining the number of synapses following exposure. Finally, the function of these neuronal connections will be tested to determine whether the immune response, possibly altered in autism, leads to impaired connectivity and circuitry.
What this means for people with autism: Changes in immune system function have been reported in individuals with autism, but the consequences of this hyperactivity on brain development are not yet well understood. These studies will lead to a better understanding of the neurobiological consequences of altered immune activity, and how they relate to ASD.
PI: McAllister (CAN Pilot Project Award, 2006)
A Role for Immune Proteins in Early Stages of Neural Development: Possible Implications for the Pathogenesis of Autism ($120,000)
Proper formation of connections in the brain during childhood provides the substrate for adult perception, learning, memory, and cognition. Tragically, improper formation or function of these connections leads to many neurodevelopmental disorders, including autism. Autism spectrum disorder is a highly prevalent severe neurobehavioral syndrome with a heterogeneous phenotype. Although there is a strong genetic component to autism, the syndrome can also be caused or influenced by nongenetic factors. Specifically, maternal viral infection has been identified as the principle nongenetic cause of autism. Several studies have even indicated a genetic link between autism and immune system genes. Since immune molecules are increased following infection and are present in the developing brain, it is possible that changes in these immune molecules lead to changes in neuronal connectivity that underlie some forms of autism. This proposal will test this idea by studying the function of altered levels of a specific kind of immune molecule on the initial formation of connections and their subsequent plasticity in the developing brain. Thus, our results should reveal a mechanism for the primary nongenetic cause of autism and thereby illuminate potential preventive therapies for this devastating disease.
What this means for people with autism: Determining the precise role of specific immune activity may elucidate an important immune mechanism leading to inflammation in CNS of autistic patients, as well as open new therapeutic possibilities for these patients.PI: McAllister (Basic and Clinical Award, 2007)
Immune molecules and cortical synaptogenesis: possible implications for the pathogenesis of autism ($450,000)
(Co-Sponsor: The Higgins Family Charitable Foundation)
Proper formation of connections in the brain during childhood provides the substrate for adult perception, learning, memory, and cognition. Tragically, improper formation or function of these connections may lead to many neurodevelopmental disorders, including autism. Although there is clearly a strong genetic component to autism, its incidence also appears to be influenced by a wide range of environmental factors. Many of these factors have in common the ability to alter immune function. Since MHCI molecules are proteins that mediate the immune response and that are also present on neurons, it is possible that changes in expression of MHCI in the developing brain lead to the cellular changes that contribute to autism.
Recently, Dr. McAllister's lab has discovered that MHCI molecules negatively regulate the initial formation of connections in the developing brain. This result is particularly exciting because it implies that environmental factors that initiate an immune response could dramatically affect connectivity in the developing brain and thereby alter cognition.
What this means for people with autism: Results from these experiments will identify whether alterations in MHCI levels could be involved in the pathogenesis of autism. Elucidating the mechanisms by which MHCI molecules act could reveal possible therapeutic targets for preventing and/or treating autism.
PI: Pessah (CAN Environmental Initiative Innovator Award, 2006)
Contribution of Calcium Channel Mutations to Autism Risk and Mercury Susceptibility ($140,000)
The goal of this research is to understand the genetic and environmental risk factors contributing to the incidence and severity of core symptoms and comorbidity seen in childhood autism. Dr. Pessah hypothesizes that mutations in specific types of calcium (Ca2+) channels may contribute to certain forms of autism and significantly increased susceptibility to adverse effects of environmental toxicants. This hypothesis is based on evidence from the Pessah lab that organic mercury, polychlorinated biphenyls, and flame retardants (PBDEs) can alter the intracellular Ca2+ signals generated by ryanodine receptors, an important type of calcium channel, and that these receptors are essential for normal maturation and function of both the immune and nervous systems. To attain these goals, mice that contain mutations for calcium channels will be studied for abnormal social behavior and their possible heightened susceptibility to organic mercury compounds such as thimerosal will be studied in detail. One mouse currently being developed possesses a mutation within a specific calcium channel (Cavl.2) that has been found to cause Timothy Syndrome (TS). Children with TS have a 60% rate of an autism diagnosis, with up to 80% of the children showing some signs of autism. Two additional mouse models are currently being studied that possess a mutation within the type 1 or type 2 ryanodine receptor Ca2+ channel (RyR1 and RyR2, respectively). Dr. Pessah's lab has found that mice possessing mutations in RyR channels have heightened susceptibility to chemically-induced adverse reactions of the immune and nervous systems. Together, the Cavl.2 and RyR2 receptors form a signaling unit in heart, neurons and T lymphocytes. This project will investigate whether these three lines of mice, which have an underlying genetic defect in Ca2+ signaling, will have increased behavioral and immunological problems when exposed to mercury, and will also examine whether mercury directly affects the development of nerve cells from these animals. Finally, the Pessah lab will determine whether children with autism have a higher frequency of Cavl.2 or RyR mutations. Collectively these experiments will provide important new information on the possible contribution of Cavl.2 or RyR mutations to autism risk in humans and launch studies of enhanced susceptibility of the developing nervous and immune systems to organic forms of mercury in mice carrying mutations relevant to autism.
Mikhail Pletnikov, M.D., Ph.D.
Johns Hopkins University School of Medicine
$120,000 for 2 years (2008)
Gene-environment interactions in the pathogenesis of autism-like neurodevelopmental damage: a mouse model
Autism likely results from a combination of genetic and environmental factors, as particular genetic variations may make an individual more sensitive to environmental factors. The present study will examine the interaction between a specific gene and an environmental factor, both known to confer risk of neurodevelopmental problems. The gene under study is DISC1, which is located in a region of the human genome likely to harbor an autism susceptibility gene. Mice with mutant versions of this gene have a predisposition to neurodevelopmental problems, which may be exacerbated or influenced by environmental factors.
One prenatal environmental factor that may modulate vulnerability to autism in the prenatal period is the maternal immune response. In this study, Dr. Pletnikov and colleagues will examine the interaction between mutations in DISC1 and the maternal immune response. They will administer a compound which mimics important aspects of the maternal immune response to viral infections to pregnant mice which harbor mutant versions of DISC1. They will examine neural development and autistic-like behaviors in the offspring of mice given the immune stimulus during pregnancy to test the hypothesis that the environmental challenge (immune activation) will exacerbate the alterations in brain development and behavior seen in DISC1 mutants.
This research may identify molecular mechanisms mediating gene-environment interactions important for neurodevelopment, which would be therefore be novel targets for the development of drugs to prevent or treat neurodevelopmental problems.
Nicholas Ponzio, Ph.D.
University of Medicine and Dentistry New Jersey
$449,997 for 3 years (2008)
Influence of the maternal immune response on the development of autism
Clinical and experimental evidence points to a role for the immune system during pregnancy in the development of autism spectrum disorders (ASD). Both T cells and cytokines (proteins which are produced by and regulate the behavior of immune cells) are implicated in various neurological disorders. Cytokines present in the maternal immune system can cross the placenta and enter fetal tissues, and this may affect fetal development. Preliminary results from the Ponzio laboratory have shown that the one such cytokine, interleukin-2 (IL-2) may affect fetal brain development, as the offspring of pregnant mice injected with IL-2 display abnormal behaviors. In the present study, these researchers will examine the role of maternal cytokines and immune cells as an environmental trigger for ASD.
Cytokines will be administered to pregnant mice by injection, and the effects on fetal brain development will be examined by behavioral testing of offspring for features selectively found in autism. IL-2 may act directly on the developing brain, or it may stimulate other components of the mother's immune system which in turn affects brain development. To determine which subsets of maternal immune cells and cytokines are stimulated by Il-2 treatment, the maternal immune system will be characterized by molecular and cell immunological techniques.
Correlating the activations of the immune system during pregnancy and the development of autistic-like characteristics in offspring will have clinical relevance for understanding the underlying causes of autism.
PI: Rall (Basic and Clinical Award, 2007)
Consequences of Maternal Antigen Exposure on Offspring Immunity: An Animal Model of Vertical Tolerance ($273,782)
How pathogens and/or altered immune responses to pathogens or vaccines are related to the etiology of childhood autism remains unresolved. Recently, a chronic neutoinflammatory response was reported in some children with autism. In separate mouse studies, it was shown that maternal exposure to viral pathogens during pregnancy could adversely influence neurodevelopment in her offspring. Whether these findings are linked, and how they relate to the onset of autism, remain unresolved.
The goal of this pilot project is to perform basic science experiments in a mouse model of central nervous system infection with measles virus (MV) to explore the potential link between maternal immune history and neuroinflammation. In preliminary experiments. Dr. Rall has shown that neonatal mice born of mothers that were previously infected with MV had increased expression of pro-inflammatory molecules, including those observed in autistic children. Moreover, the neonates appeared to be immunologically tolerant to further infection by MV. This project will further characterize these findings in greater detail to gain insight into the impact of human maternal immunity on the developing immune system of her progeny.
What this means for people with autism: This project will help define the role that altered immunity and chronic neuroinflammation play in the etiology of autism spectrum disorders.
PI: Rosenspire (CAN Pilot Award, 2007)
The Overlap Between Celiac Disease and Autism - Potential Inflammatory Responses Exacerabated by Exposure to Toxicants Such as Mercury ($60,000)
The aim of this grant is to research the connection between autism and celiac disease (CD), an autoimmune disorder of the small intestine characterized by intolerance to dietary gluten. Establishing an unambiguous link of CD to autism will allow them to pursue their hypothesis that CD may lead to inappropriate inflammation in the brain, and that patients with CD may also be especially prone to adverse inflammatory responses upon exposure to environmental toxicants such as mercury.
PI: Silbergeld (CAN Pilot Project Award, 2006)
Genetic Susceptibility to Mercury-induced Immune Dysfunction in Autism and Autism- Spectrum Disorders ($120,000)
The goal of this project is to examine genes that may affect responses to environmental risk factors in autism and autism spectrum disorders (ASD). These are complex diseases that are known to involve interactions between genetic susceptibility and acquired (or environmental) exposures. However, most research on autism/ASD development has not examined these interactions, but rather focused on either genetic or environmental risk factors, including mercury compounds. The failure to include gene-environment interactions may be one reason why we have not yet identified either key genes or significant environmental risk factors associated with autism/ASD. We plan to examine whether there are differences in how children with autism/ASD respond to one environmental contaminant (mercury) compared to their unaffected siblings and parents. We hypothesize that mercury does not cause autism by itself, but that individuals who carry certain variations in specific genes may have heightened responses to mercury, and that these variations will increase the likelihood that those children exposed to mercury will develop autism/ASD. In order to accomplish our goal, we will first develop and validate a panel of tests using immune cells found in human blood to quantitate immune responses to mercury in vitro by using the blood of healthy volunteers. Then we will apply this panel to cells obtained from children diagnosed with autism/ASD, their unaffected siblings, their parents, and unrelated community controls. This project will be the first study on this topic conducted in cells from human subjects. Eventually, we hope to identify variations in specific genes related to these responses to mercury for use in epidemiological studies of autism/ASD.
PI: Singer (Pilot Award, 2005)
Autoimmune Abnormalities in Autism: a Family Study ($120,000)
Several theories have been proposed based on the presence of antineurononal antibodies (ANAb) in individuals with autism. One study suggests that autism may be caused by the placental transfer of antibodies that, in turn, interfere with the development of the fetal brain. A second hypothesis suggests that identifying antibodies against specific central nervous system (CNS) proteins is essential in providing clues about the underlying pathophysiology. In order to further investigate the possibility of placental transfer of antibodies as a cause for autism, Dr. Singer's research will compare antibody levels in mothers of children with autism to those of unaffected children. He will also study both adult and fetal postmortem brain tissue to look at differentiation based on developmental factors.
What this means for people with autism: The identification of autoimmune abnormalities can aid in the definition of the autism phenotype, and provide new insight for physiological mechanisms behind the cause of autism as well as potential preventative therapy.
PI: Vogel (Pilot Award, 2006)
Neuroinflammation, the Kynurenine Pathway, and Autism($118, 692)
Although the causes of autism are still unknown, there is growing evidence that genetic, environmental, and immunological factors may contribute to the development of the disorder. Many cases of autism are reported to be associated with chronic activation of the immune system. This experiment will investigate markers of chronic neuroinflammation in brain tissue from individuals affected with autism. These markers will be compared to levels of two newly studied neuroactive compounds which have been associated with cell death: kynurenic acid (KYNA) and quinolinic acid (QUIN). Dr. Vogel and his colleagues will investigate if alterations in the relative abundance of KYNA and/or QUIN affect the development and functioning of neural circuits or induce damage in the nervous system thereby contributing to the development of autism.
What this means for people with autism: Alterations in immune system function has been associated with autism, however, the link between immune reactivity and onset of autism spectrum disorder has not been clearly defined. Changes in KYNA and QUIN in human postmortem tissue along with other neuropathological alterations would help better define the relationship of the immune system in brain development and neurodevelopmental disorders. These results could lead to new targets, possibly those in the immune system, for the development of novel treatments for autism.
PI: Vogt (Pilot Award, 2005)
Immune Biomarkers in Serum and Newborn Dried Blood Spots ($118,880)
At present, there are no biological tests that can be performed to diagnose autism. This study will help develop methods and establish reference ranges for measuring immune biomarkers in infants, children, and mothers that could aid in early recognition and diagnosis of autism. The researchers will investigate if autism may be caused by immune and inflammatory reactions that influence neural development during gestation and infancy. They will use the microbead suspension array (MSA), which is a flexible, highly sensitive assay system that can be used to measure multiple biomarkers simultaneously from a very small sample, such as a drop of blood. Dr. Vogt and his colleagues hope to develop a panel of reliable, transferable laboratory methods for measuring selected biological markers of the immune system in serum and dried blood spots (DBS).
What this means for people with autism: This study will help establish tests and reference ranges that are readily transferable to other laboratories, so that all research and public health investigators can make use of them. Ideally, these population- based research activities will implicate specific environmental triggers of autism and help lead to preventive measures.
PI: Wills-Karp, Malloy, Manning-Courtney (Pilot Award, 2006)
Does Immune System Dysfunction Play a Role in Autism? ($100,000)
Recent evidence suggests that the immune system, which normally protects the body against many diseases, may malfunction in people with autism and actually contribute to or produce this disorder. "Adaptive" immune "T" cells are summoned by ‘innate" immune cells to attack invaders. Immune T cells in some people, however, mistake the body's own tissues as foreign and attack them, a process called "autoimmunity." Immune T cells also can over-react to otherwise harmless substances, such as pollen, and produce allergies. Usually these potentially errant responses by immune T cells are kept under control by ‘regulatory' T cells. Regulatory T cells are produced by the Foxp3 gene. According to the collaborating researchers, who combine expertise in autism, immunity, and patterns of disease ("epidemiology"), a disproportionate number of children with autism have immune system malfunctions that are similar to those seen in autoimmunity, allergy, or both conditions. They hypothesize that regulatory T cells in people with autism may be too few, or too weak, to provide a generalized ability to control errant immune responses, which contributes to, or causes, autism.
The collaborators will study immune T cells, which circulate through the bloodstream, in blood samples taken from 20 children with autism and 20 healthy ("control") children. They will compare the number of regulatory T cells, and how effectively these cells control the "attacker" T cells, in blood samples from the two groups of children. The investigators also will find out whether differences exist in the two groups of blood samples in the amount of chemicals, called ‘cytokines," produced by attacking T cells. Excessive amounts of these cytokines, suggesting incomplete control of T cells by their regulators, may have consequences for the brain, providing a link between immune dysfunction and autism. Alternatively, some other factor may be common to both immune regulation and to autism.
What this means for people with autism: If this study indicates that a failure to properly regulate immune T cells is involved in autism, the research will provide a better understanding of immune system involvement in autism. The findings also may provide an immune "marker" to diagnose autism, and lead to development of specific immune-based therapies to prevent or treat autism.
C. Studies Which Investigate Other Environmental Factors:
PI: Ascherio (Pilot Award, 2007)
Maternal Risk Factors for Autism in the Nurses Health Study II - a Pilot Study ($120,000)
(Co-Sponsor: The Higgins Family Charitable Foundation)
Established in 1989, the Nurses Health Study II has prospectively evaluated many aspects of women's health in a cohort of over 100,000 women in the United States. The information collected on this group include medical, obstetrical, and prospectively collected dietary factors, as well as neurodevelopmental diagnosis of children born to women in this cohort. This allows for a unique opportunity to investigate a wide range of environmental factors, including maternal dietary and reproductive factors, which may be associated with risk of developing autism spectrum disorders. Diet and medical history of mothers with a child with autism, as well as those who did not report a child diagnosed with autism, will be studied using information gathered prior to pregnancy. These children and their parents will be screened using the social responsiveness scale (SRS) and then followed up by the Autism Diagnostic Instrument-Revised (ADI-R). Utility of the SRS, which measures autism severity using one quantifiable score, as a diagnostic instrument will also be investigated in this study.
What this means for people with autism: In addition to diet and obstetrical complications, this study will provide support to evaluate the feasibility of using this extensive and well-researched project to study risk factors associated with autism. This project provides a unique opportunity to use existing data in order to determine the role of environmental risk factors on neurodevelopment for a better understanding of the cause and possible preventative measures.
PI: Chen (Pilot Award, 2006)
Testing the “Extreme Male Brain” Theory of Autism ($100,000)
Autism occurs four times more frequently in males compared to females, suggesting that a complex genetic predisposition, involving hormones, is involved. According to these researchers, since females have stronger emphasizing capability, while males have stronger systemizing capability, an "extreme male brain" (EMB) theory may explain the genetic basis of autism. This theory proposes that individuals along the autism spectrum are characterized by impairments in empathy alongside intact or even exceptional systematizing capacities. The researchers suggest that endogenous hormone levels of either or both the parent and the fetus during development are important. They hypothesize that inherited genetic variations in androgen metabolism modify the risk of autism, that there is a critical time when fetal exposure to androgens, specifically testosterone, is related to later development of autism spectrum disorder.
They will test the EMB theory by undertaking genetic studies in 260 mother-child pairs in which the child has autism. First, the researchers will identify different forms of androgen-metabolizing genes that are biomarkers for integrated hormone levels. They then will assess this relationship between androgen metabolism and autism risk by analyzing forms of genes that favor the production and accumulation of testosterone. Thereafter, they will confirm whether the forms of genes identified occur in 300 healthy mother-child pairs, and whether maternal or fetal hormonal levels are key. Through this process, the researchers will derive direct evidence on whether or not the EMB theory is valid.
What this means for people with autism: If the EMB theory is validated, it would lead to further clinical efforts to assess genetic or individual susceptibility factors that increase the risk of autism, and to explore whether contributing hormonal, environmental or dietary exposures might be minimized.
PI: Dodds (CAN Pilot Project Award, 2007)
Risk for Developing Autism: A Population-Based Longitudinal Study of Obstetric and Neonatal Factors ($119,662)
Autism is part of a spectrum of disorders that are characterized by severe impairment in social interaction and communication and by the presence of inflexible behavior. Numerous reports suggest a trend of increasing rates of autism in Canada and in other countries, although it is not clear whether this increase reflects increased awareness of autism and changes in the way autism is diagnosed or whether the increase reflects true population increases in the disorder. Little is known about the causes of this disorder. Several recent studies have suggested that problems in pregnancy or in the newborn period may play a role in the development of autism. The purpose of this study is to use a population-based approach to identify pregnancy and newborn factors that are associated with the subsequent development of autism. Understanding the role of early life factors that are related to the development of autism is a first step towards early diagnosis and intervention.
PI: Happe (Mentor-based Fellowship, 2006)
From Genes to Behavior: A Multidisciplinary Investigation of the Autism Triad ($82,000)
Most research on autism spectrum disorders (ASDs) has assumed that the three core behaviors that represent ASDs—social impairments, communication, and restricted/repetitive behaviors – the “triad” are interrelated. However, it is possible that these three domains may be very different and caused by different mechanisms. This implies that different features of autism may be caused by different genes, associated with different brain regions and related to different core cognitive impairments. Dr. Happe and her colleagues, therefore propose that research is likely to learn more about ASDs by examining each of these behaviors separately.
Dr. Angelica Ronald, the post-doctoral fellow, will conduct new analyses to examine individual differences in affected and non-affected people in three domains of cognitive processing. She will also identify genetic markers and environmental factors which are associated with each core behavior. This will help better identify the causes for each symptom of autism, and determine if they can be separated from one another. Data and resources from the Twins Early Development Study, will be used to expedite findings. The post-doctoral fellow is well qualified for this project, having already published several papers on autism research and recently received the 2006 Young Investigator Award by the International Society for Autism Research.
What this means for people with autism: This research will take a novel approach to studying the gene-brain-behavior pathways in ASDs by examining the three core behavioral traits of ASD separately. If the theory holds up and different features of autism are caused by different genes, associated with different brain regions, and related to different core cognitive impairments, the findings from this study may lead to tailored interventions designed to address specific characteristics of each behavioral trait.
PI: Kim
Propsective Examination of 6-Year Cumulative Incidence of ASDs: A Total Population Study ($114,545)
The prevalence of autism has increased dramatically over the past 10 years, however, reported measures of prevalence do not accurately assess the role of the environment over better diagnostic techniques and service availability. This is better evaluated by measuring the incidence of autism over time – that is, the number of new casesinitially not diagnosed with autism, then later diagnosed with autism on a yearly basis using rigorous screening, standard diagnostic assessments and valid case ascertainment in a specific age category over successive years. In addition, the study must include a defined group and accurately assess all members of that group.
Because Korea is a relatively genetic homogeneous group as compared with other countries, and because the investigators have established the parameters listed above in their previous studies investigating autism in a geographically defined region in a large group of people, this is an ideal situation to examine the changes in incidence and prevalance over time. The investigators in Korea and in the US have already developed methods to identify, screen and diagnose children with autism using a grant from Autism Speaks in 2005. Therefore, this project will allow Dr. Kim and her colleagues to analyze incidence rates over time in 6 year olds with autism in Korea.
What this means for people with autism: Both the ongoing and proposed research is potentially modeled for state-of-the-art epidemiological research on ASDs across cultures. Along with the ongoing prevalence study, the proposed study will provide incidence proportions of ASD up to age 6 among four consecutive birth cohorts. This pilot study, along with futuresurveillance studies, will pave the way to answering critical questions about the cause of the increase in autism over the past decade
PI: Kinney (CAN Pilot Project Award, 2005)
Do Environmental Factors Play a Role in Autism? A Test Using Natural Experiments ($80,000)
Whether environmental factors play an important role in causing autism is a crucial - and hotly debated - question. Many studies report unusually high rates of medical problems during the gestations and births of persons who later developed autism, suggesting that environmental factors occurring before or around the time of birth may contribute to the development of the disorder. Skeptics, however, argue that the same genes that cause autism also cause these high rates of pregnancy and birth complications. The most powerful scientific approach to deciding this issue -- an experiment in which pregnant women were randomly assigned to low vs. high stress conditions - would clearly be unethical. We use an alternative strategy that uses natural disasters as "experiments of nature" to test the hypothesis that exposure to stressful events during vulnerable weeks of gestation significantly increases risk of developing autism. Anonymous data on more than 4,000 persons with autism from three different states, as well as on 2 million general population births in these same states, will be studied to investigate whether autism rates are significantly increased among individuals who were in certain weeks of gestation at the time their mothers were exposed to natural disasters such as extremely destructive earthquakes, hurricanes, and severe blizzards. Confirmation that pre- and perinatal environmental stressors play a significant role in causing autism would have important implications for the treatment and prevention of autism.
PI: Lee (Basic and Clinical Research, 2007)
The Development of Chinese Versions of the ADOS and ADI-R ($450,000)
Of the available standardized diagnostic instruments for autism spectrum disorders, the Autism Diagnostic Observational Schedule (ADOS) and the Autism Diagnostic Interview- Revised (ADI-R) are the most commonly used. Currently, both the ADOS and ADI-R are available in twelve languages, and although Chinese mandarin is the primary language for 1.2 billion people worldwide, it is not available in this language. A previous project completed by a team of experts assembled by Dr. Lee has collected preliminary data from translated screening instruments such as the SCQ had identified cultural factors which should be modified to make the testing instrument valid. The unavailability of proper diagnostic tools in Chinese has been one of the major barriers for autism researchers who conduct research in Chinese speaking populations. To fill the gap and facilitate future autism research in Chinese speaking populations, this application will both translate and adapt the ADOS and ADI-R into Chinese mandarin and train Chinese-speaking clinicians to become research reliable on these diagnostic instruments so a later prevalence study can be conducted in this country.
What this means for people with autism: Data collected using the Chinese versions of the ADOS and ADI-R will allow multi-national and multi-racial/ethnic comparisons in variations and similarities of ASDs using the same diagnostic criteria and case definitions. This will allow researchers to examine the prevalence and incidence of autism in a country with different genetic and environmental factors to better understand the causes of autism.
PI: Nair (Special Project, 2006)
Neurodevelopmental disabilities among children in India($100,000)
Given current epidemiologic estimates, there are approximately 1.7 million individuals with autism in India. The primary objective of this research project is to assess the screening and diagnostic prevalence of neurodevelopmental disorders, including autism, in children between the ages of 2-9 in India and gain information on risk factors in these children. The investigators will develop a novel neurodevelopmental disability screening tool and consensus clinical criteria, and validate these instruments so that they can be used in as a diagnostic instrument for further evaluation of the prevalence of autism in this country. In addition to studying the prevalence of autism in Indian, the investigators will also identify the full clinical spectrum of autism using their test instruments. In addition to case ascertainment, potential risk factors for autism, including infections, nutritional deficiencies and genetic factors will be identified through open ended interviews with health personnel.
What this means for people with autism: The identification of an initial nation-wide developmental disability cohort would allow more refined characterization of the Indian autistic population, setting the stage for exploring future scientific opportunities in causes (more comprehensive epidemiology and genetic studies), diagnosis (Baby Sibs), and treatment (clinical trials) in that country. By generating valid data from India, capturing socio-cultural and geographical variability, researchers can better identify the true worldwide prevalence of autism and further quantify risk factors which may contribute to these differences.
PI: Patterson (Mentor-based Fellowship, 2006)
Role of Cytokines in Mediating the Role of Maternal Immune Activation in the Fetal Brain ($52,000)
Children whose mothers develop infections during pregnancy are at increased risk for autism, schizophrenia or other neurodevelopmental disorders. However the molecular pathway that leads from infection to autism is unclear. Using an animal model of maternal viral infection, Dr. Patterson have shown that the maternal immune reaction, rather than the virus itself, interferes with fetal development leading to behavioral symptoms of heightened anxiety and decreased social interaction.
This experiment will establish which specific immune factors interfere with fetal brain development. Four different immune factors will be tested to produce and then reverse early behavioral deficits in offspring exposed in utero to these immune factors. Any immune factor that meets both criteria will be a leading candidate for continued research into specific molecular pathways that interfere with normal development and lead to autism-like symptoms.
What this means for people with autism: This project will use a mouse model of a known risk factor for autism—maternal viral infection—to determine a mechanism that elicits changes in fetal brain development and leads to the autistic phenotype. These findings could lead to a better understanding of what goes wrong in autism, and suggest potential methods of preventing the disorder.
PI: Rakic (Mentor-based Fellowship, 2006)
Effects of a Non-Steroidal Anti-Inflammatory Drug on Neuronal Migration ($101,000)
While the precise causes of autism is not yet known, multiple genetic and environmental factors are thought to play an important impact on the development of the disorder. The site where certain neurons connect, called gap junctions, are sensitive to environmental agents and have downstream effects on cell growth and reproduction, and possibly on migration of neuronal precursors to their appropriate destinations. In order to manipulate the function of the gap junction in an animal model, the investigators will test the effects of an NSAID which alters the function of gap junctions on the activity of neurons during development and migration. Deficits in neuronal migration and formation of different layers of the cortex may lead to the neuropathological and behavioral features observed by other scientists.
The mentor and the fellow will use advanced molecular biology techniques to trace the position of the migrated neurons during critical periods of neuronal development. They will also study properties of the misplaced neurons to determine their abilities to participate in a functional network. Finally, behavioral analysis of offspring exposed to prenatal NSAIDS will be performed. This will help better link any neurobiological differences with functional outcomes, especially as they relate to the symptoms of autism spectrum disorder.
What this means for people with autism: Using disruption of the gap junction by biophysical and environmental factors will help identify the cause of cortical malformation. This will be relevant to a better understanding of brain development as well as the causes of autism spectrum disorders
PI: Schmitz (Pilot Award, 2005)
Cytoarchitectural Alterations in the Cerebral Cortex in Autism($120,000)
Dr. Schmitz's lab has been studying the neuropathological characteristics of autism for many years. His group has reported abnormalities in size, number, and organization of neurons in the cerebral cortex. This current study will utilize novel tools to view the organization of cells in the cortex in three dimensions, specifically examining the connectivity of neurons between different areas of the cortex. Furthermore, his lab will compare these changes with those of a current animal model of autism: in utero maternal influenza virus exposure.
What this means for people with autism: The results of the proposed project will contribute to a better understanding of the neuropathology of autism using software which will be made available to the research community. In addition, this study will investigate the validity of an animal model of autism where environmental factors play a key role.
PI: Sourander (Pilot Award, 2007)
Early Developmental Risk Factors for Autism in a National Birth Cohort ($119,075)
This pilot study will establish a new project called the Finnish Prenatal Study of Autism and Autism Spectrum Disorders (FiPS-A). The FiPS-A is based on the Finnish Maternity Cohort (FMC), which consists of virtually all births in Finland (N=1.1 million) from 1987- 2005. The investigators will use maternal medical and exposure history collected during pregnancy to examine if infection, hormonal abnormalities and smoking are related to an increased risk of autism in their children in a subset of these 1.1 million births. This study will also be able to identify potential early risk factors including improper growth and development before the child was diagnosed to assess whether these parameters can be included in early signs of autism. In addition to medical data, this project has the ability to analyze blood samples that were drawn during pregnancy in a random sample of children who are diagnosed with autism, and a random sample of children without autism, all of whom were in the national FMC cohort.
What this means for people with autism: This project has the potential to become one of the largest epidemiological studies to investigate prenatal and perinatal risk factors in autism, including a large biomarker repository to isolate possible early prenatal risk factors. In addition to studying the longitudinal development of children who later develop autism, multiple environmental factors, including medical information from the mother and child, will be studied for further analysis.
PI: Windham (Pilot Award, 2006)
Autism and Prenatal Hormone Markers($60,000)
The California Department of Health Services is currently tracking the prevalence and demographic characteristics of autism. This data will be linked to hormone and protein markers measured during pregnancy. This is made possible though the California prenatal screening program, in which several hormones or protein markers were measured in maternal blood during the second trimester. In the proposed study, the levels of these hormone/protein in nearly 2,000 pregnant women and their offspring who are later diagnosed with autism, compared to the nearly 600,000 screened births during the same two years. Although hormonal factors have been frequently suggested as contributing to the occurrence or severity of autism, few studies have investigated this hypothesis.
What this means for people with autism: The results will help shape further research to rigorously evaluate complex interactions between genetic factors, in utero hormonal factors, and environmental factors in relation to autism. In addition to the analyses proposed, the investigators have numerous opportunities for follow-up, including examining similar parameters in other birth years, examining other newborn screening markers, and potentially obtaining newborn blood spots for genotyping. The proposed study provides a unique and cost-effective opportunity explore important data on a very large population.
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