In 2000, NAAR became the first non-governmental organization to break the $1 million mark for funding autism research and committed approximately $1.5 million to fund 19 pilot studies and two mentor-based fellowships in autism research taking place in the United States and Spain. Also in 2000, NAAR and the Nancy Lurie Marks Family Foundation began sponsoring the Autism Genetics Cooperative, an annual retreat for an international consortium of the world's leading genetic researchers focusing on autism to share information and combine data to accelerate the search for autism susceptibility genes.
David G. Amaral, Ph.D.
University of California-Davis, Davis, CA
"Postmortem Neuroanatomical Evaluation of the Amygdaloid Complex in Autism"
Two-Year Award: $68,000
Research Partner: Autism Society Cincinnati
Infantile autism is a neurobiological disorder that severely disrupts social, cognitive, and language development. While studies have hinted that alterations in the section of the brain called the "amygdala" underlies the social and emotional abnormalities in autism, a complete analysis is long overdue. This study, under the direction of Dr. David Amaral, will evaluate this hypothesis with a complete quantitative analysis of the atypical neural organization in individuals with autism. Using brain samples provided by the Autism Tissue Program, his group will actually count the number of neurons in each subdivision of the amygdala, comparing sizes and shapes. They will then extend their analysis to determine subtler neurochemical abnormalities. If a relationship is confirmed, changes in the structure of the amygdala may prove to be a useful in the diagnosis of autism using safe noninvasive imaging techniques.
Gene J. Blatt, Ph.D.
Boston University Medical School, Boston, MA
"Cerebellar Circuitry in Autism".
Two-Year Award: $94,878
Research Partner: Nancy Lurie Marks Family Foundation
Previous studies have indicated that in part of the brain called the "posterolateral cerebellar cortex", there is a reduction in number of a specific type of cells called "purkinge" in individuals with autism. The missing cells raise interesting questions such as: Were the purkinge cells ever produced? Is it a specific type of purkinge cell that is affected? What happens to the typical connections purkinge cells make with other brain cells? Studying the circuitry of the purkinge cells may allow researchers to understand the developmental timing of autism, and understand the areas susceptible to intervention. Dr. Blatt and his colleagues intend to evaluate the changes in the integrity of autistic purkinge cells and determine any morphological differences. A part of the brain called the "inferior olivary nucleus" will also be evaluated, as it normally sends projections to the purkinge cells. Studies will be performed through histochemical methods to illuminate the specific properties of the purkinge cells.
Ira L. Cohen, Ph.D.
New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY
"Epidemiology of Autism on Staten Island".
Two-year Award: $79,504
Although the causes of autism are unknown, there has been a heightened concern among parent groups, the media, and medical professionals about exposure to environmental toxins. Dr. Ira L.Cohen and his colleagues will shed light on the impact of environmental factors by investigating a disproportionately high incidence of autistic individuals in the Staten Island area, where there is a large number of toxic waste sites situated within a small geographical region. Population data will be used to identify two hundred children with autism between the ages of 6-12. Through diagnostic tools (ADI and ADOS-G), these previously reported cases of autism will be reevaluated to ensure a correct initial diagnosis. This study has direct relevance to previous studies, such as the evaluation of Brick Township N.J., where a disproportionately high incidence of autistic individuals was reported.
John N. Constantino, M.D.
Washington University School of Medicine, St. Louis, MO
"A Quantitative Genetic Measure of Autistic Traits".
Two-Year Award: $58,762
Research Partner: Autism Coalition for Research & Education
Currently diagnostic measures of autistic spectrum deficits focus on establishing a definitive diagnosis of autism. However, clinical studies have suggested that autistic disorder represent the upper extreme of quantitative traits that are variably distributed in the population.
Dr. John N. Constantino and his collegues have developed the Social Reciprocity Scale (SRS) that was designed to ascertain autistic symptoms across the entire spectrum of the autistic disorder, from unaffected to the severely affected. In this study, the SRS was validated by strict comparisons with the Autism Diagnostic Interview-Revised (ADI-R), the only diagnostic tool for autism spectrum disorders which has been standardized, rigorously tested and universally recognized as a "gold standard" for supporting the diagnosis of autistic disorder. The SRS could feasibly be used to study the genetics of autism in whole populations, given its ease of administration and its known psychometric properties in epidemiologic samples of children. It takes only 15-20 minutes to complete and can be done so by parents and/or teachers. The SRS may have very important clinical utility in quantifying and characterizing autistic spectrum traits, which are sub threshold for the full diagnosis of autism and be useful for monitoring the effects of treatment of autistic spectrum disorders.
Deborah A. Fein, Ph.D.
University of Connecticut, Storrs, CT
"Early Detection of Pervasive Developmental Disorders"
Two-Year Award: $70,658
Research Partner: Autism Society of America Foundation Morton
With currently available diagnostic instruments, autism is difficult to detect in very young children. The average age at which parents express first concern to their pediatrician is 17 months, but the average age of diagnosis is 4 years. Since there is evidence exists that early detection and intervention can lead to substantially better prognosis, this is clearly an issue. The first diagnostic tool specifically designed to screen for autism was the British Checklist for Autism in Toddlers (CHAT), designed for 18 month old children. Despite the major advance represented by the development of the CHAT, several modifications to itsÕ structure were considered advantageous for further development of this early screening technology.
Dr. Deborah Fein and her colleagues have addressed the limitations and shortfall of the CHAT and developed a comprehensive version referred to as the M-CHAT (Modified Checklist for Autism in Toddlers). This study involves the validation of this new widely usable, screening tool for autism, which assesses 23 items in a checklist format to use at the childÕs 24 month checkup to determine cognitive, language, and adaptive functioning. Furthermore, the study will investigate parameters of more successful treatment programs for young children with autism.
Ann Gernsbacher, Ph.D. & H. Hill Goldsmith, Ph.D.
University of Wisconsin, Madison, WI
"Toward a Dyspraxic Subtype of Autistic Spectrum Disorder".
Two-Year Award: $96,571
Research Partner: Nancy Lurie Marks Family Foundation
Even when diagnosed according to strict and consistent criteria, symptom profiles of persons with autism vary greatly, suggesting that the cause of autism has many origins. Therefore there is value in identifying possible subtypes of autism and to focus research on these subtypes.
Dr. Ann Gernsbacher is interested in investigating developmental verbal dyspraxia (DVD), a disorder resulting in difficulty coordinating and sequencing the oral-motor movements necessary to produce and combine speech sounds, and a common affliction in autistic individuals. For this project, she and her collegues will identify and validate a DVD subtype of autism by screening all children with autism (under age 18) in a metropolitan area. They will collect extensive behavioral, medical, and developmental histories of all the children, obtain neuroanatomical (structural MRI) data; and collect DNA for future candidate gene studies. Indices of the DVD subtype will be constructed using current diagnostic tools (e.g., the ADI and A-DOS).
Scott E. Hemby, Ph.D.
Emory University, Atlanta, GA
"Gene Expression Profiling of Autism: Alterations in Temporal Lobe Profiles".
Two-Year Award: $70,658
Research Partner: Madeline & Arthur Millman, on behalf of the Autism Society of America Foundation
Despite considerable research effort over the past several decades, identifying the neuropathology underlying the behavioral abnormalities related to autism remains elusive. It is feasible that the changes in brain function are subtle and correspond to alterations at the molecular level in discrete brain regions, or even in specific brain cells, leading to pronounced changes in brain function.
Several studies indicate dysfunction of the temporal lobe of the brain in autism, specifically, the hippocampal formation and entorhinal cortex. Under the supervision of Dr. Scott E. Hembel, this study will assess alterations in gene expression in these areas of the brain using rhesus monkeys and post-mortem tissue from autistic individuals. Rhesus monkeys serve as good models to study autism, as they can produce associated behaviors when introduced into social groups, such as, social withdrawal and repetitive and stereotypic behaviors. The proposed experiments will utilize state of the art molecular biology procedures, including cDNA microarrays, to assess regional and single cell gene expression and provide information thus far unattainable. Identification of altered expression of multiple genes should establish a "fingerprint" of the molecular changes in autism and provide new targets for interventions.
Cynthia R. Johnson, Ph.D.
University of Pittsburgh, Pittsburgh, PA
"Assessment and Treatment of the Cognitive Basis of Behavioral Impairments in Autism".
Two-Year Award: $40,218
Research Partner: Pittsburgh Friends of NAAR
Individuals with autism very frequently experience challenging behaviors that greatly interfere with optimal learning. Furthermore, behavior impairment such as aggression, self-injury, and disruption very often result in more restricted educational settings. While the accumulated behavioral research on assessment and treatment has been of value, the recognition of the cognitive underpinnings of problematic behaviors in autism has been virtually ignored.
Dr. Cynthia R. Johnson and her colleagues will examine several cognitive factors and relate these factors to behavioral impairments in high functioning autistic and Aspergers adolescents with verbal and full scale IQs of 80 or greater. The elucidation of these likely complex relationships has significant implications for advancing our understanding of the neurobiological mechanism driving behaviors. This study will also apply cognitive mediated treatment procedures focusing on skills such as problem solving, time management, planning and flexibility. If successful, this treatment will aid in the improvement of school performance by attenuating the display of problematic interfering behaviors and serve as a guide for development of future treatments that can intervene earlier and more effectively.
William G. Johnson, M.D.
UMDNJ–Robert Wood Johnson Medical School (New Brunswick, NJ)
"MHC Extended Haplotypes as Risk Factors for Autism".
Two-Year Award: $80,000
Research Partner: Doug Flutie, Jr. Foundation for Autism, Inc.
A group of genes called the major histocompatibility complex (MHC) located on chromosome 6 is a major risk factor for autoimmune diseases. There is evidence that the MHC is also a risk factor for autism. In fact, it has been suggested that certain clusters of MHC genes called "extended haplotypes", give the highest relative risk of any genetic risk factor for autism yet identified. Unfortunately, this information comes from a study design (allelic association) that can give false positive results.
Using a robust study design called "transmission disequilibrium", Dr. William G. Johnson and his colleagues intend to resolve this issue and determine the frequency of autoimmune disorders in individuals with autism and their family members. In this method, the transmission frequencies of traits from parent to child are compared with those expected by chance. The use of internal controls avoids the problem of population stratification. Using this same technique, Dr. Johnson's group has recently shown an increased frequency of autoimmune diseases and other developmental disorders in individuals with spina bifida. The current study will provide insight into the mechanism by which autoimmune disorders are risk factors for autism and test the hypotheses that certain MHC extended haplotypes are risk factors for autism that act indirectly through mothers during pregnancy.
Ami Klin, Ph.D.
Yale University Child Study Center, New Haven, CT
"Visual Scanning Patterns and Mental Representations of Social Interaction in Infants and Toddlers Suspected of Having Autism"
Two-Year Award: $97,080
Research Partner: Toys R Us, Inc.
Advances in psychological research of the core social deficits in autism have increasingly focused attention on disruptions of early-emerging skills that appear to derail from the normal development of socialization. However, there is a lack of quantifiable indices of social competence that could define a spectrum of social outcomes, from normality to varying manifestations of autism. This hinders genetic and neurofunctional research, which partially rely on such indices for interpretation of heritability and neuroimaging data.
This study, under the direction of Dr. Ami Klin, focuses on the inability of autistic children to visually orient themselves to social stimuli, and transfer that information to create mental representations. This process is a key requirement to subsequently produce normal social interactions. The investigators will use a novel method that measures visual scanning patterns in response to real life social interactions. A non-invasive eye-tracking device will measure the specific location in which an infant is focusing during social situations. The capacity of the infant to create mental representations can be evaluated via computerized animations. This strategy will also quantify any atypical strategies of social monitoring and will bring experimental measures into line with clinical observations.
Jeffrey D. Macklis, M.D., D.
HST Children's Hospital/Harvard Medical School, Boston, MA
"Neocortical Callosal Projection Neuron Survival and Differentiation Control".
One-Year Award: $50,000
Research Partner: Audrey Flack & H. Robert Marcus, on behalf of the Autism Society of America Foundation
The major communication pathway between the two hemispheres of the brain is through the corpus callosum, where specific connections by cells called "callosal projection neurons" (CPN) are thought to underlie high-level associative cognitive function that is compromised in autism. There are both strong theoretical reasons and significant recent evidence to support the hypothesis that abnormal development of CPN could play an important role in autism spectrum disorders. Abnormalities of these neurons have been reported in autistic patients by multiple investigators. However, such analysis has been hampered by the overwhelming diversity of cell types and inability to isolate them.
In this study, Dr Jeffery D. Macklis and his colleagues have used a novel method, using retrograde fluorescence labeling and fluorescence-activated cell sorting (FACS), to successfully isolate CPN from mice. By isolating the purified CPN from embryonic and postnatal mice at distinct stages of development, they have shown that the purified CPN survive for weeks, acquire stage-specific morphologies, and express appropriate neurotransmitters and growth factor receptors. Furthermore, their studies have demonstrated that depending on the development stage at which the CPN are isolated, there is a dependence to exogenous factors. The researchers intend to build on this pilot data and elucidate which specific genes, both known and novel are differentially expressed during these progressive steps of development.
Ron C. Michaelis, Ph.D. J.C.
Self Research Institute, Greenwood Genetic Center, Greenwood, S.C.
"Mapping the Breakpoints of a Balanced Translocation, t(9:15)(q32;q22), in a Patient with Autism".
Two-Year Award: $57,475
Research Partner: Pittsburgh Friends of NAAR
Genetic studies indicate that many different genes are likely to contribute to the risk of developing autism and that the extent each of these genes are involved may vary from person to person. So, trying to determine which genes are related to autism is very complex. However, as noted bellow, there are some resent findings that may help in this effort.
Dr. Ron C. Michaelis has been working with an autistic individual who has a balanced genetic translocation involving chromosome 9 and chromosome 15; that is, pieces of DNA have broken off during early embryonic development and switched places. Individuals with balanced genetic translocations represent valuable resources for determining specific genes responsible for developmental disorders as these translocations usually result in disruption of the activity of a gene at the site of the translocation. To add to this, other studies have suggested that this region in chromosome 15 contains several genes that are potentially involved in autism. To identify the genes disrupted by the translocation, Dr. Michaelis and his collegues will physically map the translocation breakpoints and analyze the DNA sequence surrounding the breakpoints.
Yan Ni, Ph.D.
University of Texas-Southwest Medical Center, Dallas, TX
NAAR/Bristol-Myers Squibb Research Fellowship in Autism and Neuropharmacology.
One-Year Award: $60,000
Sertraline and fluoxetine are among the most effective drugs for alleviating irritability, aggression and repetitive behavior in autistic adults. These drugs affect the uptake of Serotonin (SHT). Presently, one of the best-replicated neurochemical changes in psychiatric research is the elevated blood SHT levels (hyperserotonemia) in autistic individuals. Since most (99%) of blood SHT is stored in the platelets (blood cells), hyperserotonemia studies have focused on SHT metabolism and platelet SHT uptake. The majority of evidence indicates that SHT metabolism is unaltered in autistic individuals. This strongly suggests that platelet handling of SHT is changed. However, despite much effort, no conclusions can currently be made regarding the rate of platelet SHT uptake in autistic patients.
Dr. Yan Ni hypothesizes that altered levels of platelet SHT in hyperserotonemic autistic patients are due to changes in function and/or expressions of the platelet 5HT uptake system and that altered expression levels of SHT transporters and SHT receptors will be present in the postmortem brain tissues from autistic patients. He and his collegues will assess the role of both pre- and post-synaptic components of the serotonergic system in autism. Specifically, they will examine whether there are changes in the function and expression levels of the SHT transporter.
Jorge J. Prieto, M.D., Ph.D.
Universidad Miguel Hernandez (Spain)
"A Microscopical Study on the Neuroanatomical Abnormalities of Language-Related Cortical Areas in Autistic Patients".
Two-Year Award: $66,000
Research Partner: Nancy Lurie Marks Family Foundation
Previous studies have demonstrated abnormalities in different parts of the brain in autistic individuals, including the cerebral cortex. Dr. Jorge Prieto hypothesizes that alterations in hearing and language may be due to a disorganization of cortical architecture. Working with tissue from the Autism Tissue Program, his research group will investigate the anatomy of neurological tissue of autistic brains. Several parameters will be investigated including the gross anatomical alterations of the auditory cortex, the microscopical organization of the cerebral cortex in the Wernicke and Broca's areas, and the possible changes in the cortical circuitry involving the pyramidal cells and interneurons. Through the techniques of stereology and immunocytochemistry, Dr. Prieto will attempt to elucidate the existence of morphological changes that could be responsible for the functional alterations and behavioral impairments seen in autism.
Raju K. Pullarkat, Ph.D.
New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY
"Neurochemical Studies on Infantile Autism".
Two-Year Award: $49,973
With the recent availability of frozen autopsy brain samples, it is now possible to carry out a systematic search for the neurochemical changes in autism. Dr. Raju K. Pullarkat has previously shown a consistent protein change in the brains of autistic individuals of different ancestory, one Asian-American, one African-American, and one Caucasian. In specific, they have found a 29 kDa protein is missing and another 36 kDa protein is present.
In this study, under the supervision of Dr. Raju K. Pullarkat's, the 29 kDa and 36 kDa proteins will be isolated and characterized and it will be determined whether abnormalities of these proteins can be used as diagnostic markers for autism. To reach this goal, these proteins will be purified using classical chromatographic approaches. In order to evaluate the diagnostic potential, levels of these proteins will be determined in cultured lymphoid cells from patients with autism, their parents, and their siblings. This study could also lead to the identification of a gene related to autism and aid in the development of a biochemical method of diagnosis.
Moyra Smith, M.D., Ph.D.
University of California-Irvine, Irvine, CA
"Analysis of Chromosome 15q22 Deletion Associated with Autism and Immune Deficiency".
One-Year Award: $30,000 (continuation grant)
In a prior research study funded by NAAR, under the direction of Dr. Moyra Smith (see 2001 sponsored research), it was suggested that the autistic behavior of the subject in the study was due to interruption or rearrangement of a specific series of genes within the 15q22-15q23-genome region. The present study focuses on the identification of the specific genes which when deleted or structurally rearranged can lead to altered neural development characteristic of autism. Through gene mapping and sequencing, this analysis will determine the relevance of the genes in the 15q22-q23 and the 15q11-q12 chromosomal regions to autism.
James S. Sutcliffe, Ph.D.
Vanderbilt University Medical Center, Nashville, TN
"Modeling Autism-Related Chromosome 15 Duplications in the Mouse".
Two-Year Award: $100,000
Genetic studies indicate that many different genes are likely to contribute to the risk of developing autism and that the extent each of these genes are involved may vary from person to person. So, trying to determine which genes are related to autism is very complex. However, there are some resent findings that may help in this effort. One such example is the finding that there is a small population within the autism community that have an extra copy of a portion of DNA on a chromosome. This results in a duplication of the genes in this area.
Dr James Sulcliffe and his collogues intend to use an approach, similar to one that has been proven to be successful in studying Down's Syndrome, to identify which genes within the duplicated segment of chromosome 15 are related to autism. They will generate several lines of mice that carry an extra copy of mouse or human DNA containing only one of the genes from the segment. Each of the lines will then be observed for behavioral and neurological changes. Each change that is related to autism can then be associated to the specific gene.
Fred R. Volkmar, M.D. & Katarzyna Chawarska, Ph.D.
Yale University Child Study Center, New Haven, CT
"Precursors of Joint Attention Skills in Autism and Related Conditions".
Two-Year Award: $62,337
Research Partner: Nancy Lurie Marks Family Foundation
Most screening tools used for early identification of autism, include testing the capacity for sharing attention to an object of mutual interest. This is referred to as "joint attention" and is considered a key basic skill providing the foundation for communicative and social-cognitive development. Deficits in joint attention are profound and virtually universal in children with autism. Deficits are detectable in the second year of life, appear stable over time, and are independent from level of intelligence. However, the mechanisms underlying joint attention deficits are still poorly understood.
Dr. Fred Volkmar proposes to classify and measure the precursors of joint attention skills. In this study, he and his collegues will identify any differences in the profiles of infants with autism, developmentally delayed non-autistic children, and neurotypical children. In specific, they will investigate; a) the capacity to spontaneously follow the gaze of others to objects and events, b) the capacity for engaging in eye to eye attention with others, and c) using the gaze of others to regulate oneÕs own behavior. This will elucidate the origins of gaze abnormalities in autism, and contribute to the design of new investigative instruments to discover autism in its early stages.
Ching H. Wang, M.D., Ph.D.
University of Missouri, Columbia, MO
Roland D. Ciaranello, M.D.
Memorial Career Development Award in Basic Research.
Two-Year Award: $100,000
To regulate the level at which any gene is expressed, many control factors have to be acting together to achieve the appropriate levels of power and refinement. Genes whose expression depends on parental origin are called "imprinted genes" and are controlled by DNA methylation, i.e. the addition of a small "tag" called a methyl group on one of the bases that make up the DNA code. Since two of the autism candidate loci, 7q31-32 and 15q11-13 both contain imprinted genes, it has been hypothesized that autism may ensue from the abnormal DNA methylation and expression of these genes.
Dr. Ching and his collegues intend to implement a novel approach to identifying methylated genes, termed "differential methylation hybridization". Abnormally methylated areas will be isolated from DNA samples from autistic individuals, and compared (by hybridization) to control samples. Microarray membranes will then be used, and clones exhibiting abnormal hybridization will be identified and sequenced. These sequences will be used to search for associated genes in the genome database. Gene expression will be analyzed using autistic and control tissues, to confirm the abnormal function of these genes. This innovative approach will elucidate genetic information about autism unattainable through previous traditional techniques.
Larry J. Young, Ph.D.
Emory University, Atlanta, GA
"An Oxytocin Knockout Mouse Model for Social Deficits".
Two-Year Award: $71,250
The hormone oxytocin has been linked to cognitive and behavioral processes related to social attachment. Research suggests that maternal bonding, and pair bonding in monogamous species is attributed to oxytocin levels. Previous studies have found that autistic children have 50% less oxytocin than neurotypical children. Dr. Larry Young and his collegues intend to determine the relevance of oxytocin levels in autistic individuals. His group has previously shown that by decreasing oxytocin levels in mice resulted in isolation from mother and littermates along with a decreased recognition of littermates. Through the use of genetically engineered mice without the oxytocin gene, this project will determine the nature of the oxytocin deficit, and examine other social behaviors.
Deborah A. Yurgelun-Todd, Ph.D.
McLean Hospital/Harvard Medical School, Boston, MA
"Visual Spatial Attention in Autism: An fMRI Study".
Two-Year Award: $82,259
Autistic individuals show a marked deficit in the ability to rapidly shift visual attention between spatial locations and in engaging visual attention in the presence of distracters. The relations between regions of the brain that involved in directed attention have yet to be explored. In this study, Dr. Yurgelun-Todd and her colleagues will use functional magnetic resonance imaging (fMRI) to determine which parts of the brain are activated when autistic and non-autistic subjects view moving objects. Preliminary data presented at the 2001 International Meeting for Autism Research (IMFAR) show activation in non-autistic subjects include contralateral (opposite side) activity of the "inferior occipitotemporal" brain region, as well as ipsilateral (same side) activity of the posterior intraparietal " brain region. Autisic individuals, however, show an absence of lateralised attentional activity in the occipitotemporal region and a higher level of lateralised attentional activity of the posterior intraparietal region. Dr. Yurgelun-Todd suggests that during conditions that demand a rapid shift of visual attention, autistic individuals compensate for their impaired selective attention with a generalized arousal that results in the input of more irrelevant stimuli.
