Archived | Autism Speaks: High Risk, High Impact Projects (Winter 2008) | Circa 2008 #NotAnAutisticAlly

2008 Environmental Factors Awards
2008 Basic and Clinical Awards (Winter)
2008 Basic and Clinical Awards (Summer)
2008 Epidemiology Awards
2008 Fellowships
2008 High Risk, High Impact Projects
2008 Pilot Awards (Winter)
2008 Pilot Awards (Summer)
2008 Treatment Awards

Doug Wallace, Ph.D., UC Irvine
Richard Haas, M.D., UC San Diego
Beatrice Golomb, M.D., Ph.D., UC San Diego
$690,460 for 1 year

Mitochondrial Etiology of Autism

The investigators propose to test the hypothesis that defects in mitochondrial function may be an important factor in ASD pathophysiology. Physiological and biochemical evidence of mitochondrial dysfunction will be directly assessed by collecting skeletal muscle, assaying for mitochondrial function and quantifying oxidative stress.

Subjects will be further evaluated for mitochondrial dysfunction using five non-invasive techniques, which have the potential to supplant the muscle biopsy in diagnosis of mitochondrial dysfunction. These non-invasive tests include analysis of alterations in metabolite levels in urine and blood (metabolomics), determination of changes in brain and muscle high energy phosphates by magnetic resonance spectroscopy (MRS), determination or patient exercise capacity and resulting alterations in hormone levels, analysis of exhaled organic molecules, and analysis of changes in mitochondrial status by transdermal near infrared light absorbance.

To determine if alterations in mitochondrial genes contribute to the development of ASD, the investigators will screen subjects for alterations in mitochondrial genes that are located in chromosomal regions previously implicated in autism. Analyses will also include mtDNA copy number and changes in the mtDNA sequence that may correlate with disease. 

What this means for people with autism:

Demonstration that individuals with ASD have mitochondrial defects could provide important insights into both regressive and progressive aspects of the clinical course of ASD in children and adults. In sum, this research program is in position to develop novel methods for diagnosis of metabolic abnormalities and offer immediate treatment approaches. 

April Benasich, Ph.D., Rutgers University
Valerie Schafer, Ph.D., City University of New York
$422,387 for 2 years

Assessing information processing and capacity for understanding language in non-verbal children with autism

Individuals with autism who are non-verbal are not included in research studies and hence very little is known about their abilities. The paucity of studies is due to logistical issues that include presumed compliance difficulties and the lack of expertise among researchers who can design and implement studies in individuals who may comprise 30-50% of the ASD population.

The ability to perform research in this area is also greatly hindered because most instruments designed to assess individuals with ASD require expressive language skills. When applied to the non-verbal population, individuals typically score at the lowest levels on cognitive tests and are considered “low-functioning”.

This characterization occurs despite reports from family and caregivers that receptive language is indeed quite functional in some of these individuals. The proposal from Dr. Benasich and colleagues will utilize research strategies to directly assess the capacity for receptive language in non-verbal individuals with autism at a range of ages using EEG and information-processing tasks that they have previously developed for studying other developmental disability populations.

These experiments will be, to our knowledge, the first that are dedicated to assessing receptive language capabilities in a population of subjects that lack functional language output capabilities. 

What this means for people with autism: 

Our understanding of cognitive functions in individuals in ASD is based almost exclusively on studies involving individuals who are characterized as “high functioning”.

The proposal will characterize the cognitive abilities of a very neglected subgroup of individuals with ASD and bring needed expertise to helping individuals who have been deemed “low-functioning”. Information regarding their actual cognitive abilities could revolutionize the way these individuals are educated.

Connie Kasari, Ph.D., UCLA
Ann Kaiser, Ph.D., Vanderbilt
Rebecca Landa, Ph.D., Kennedy Krieger Institute
$1,713,958 for 3 years

Developmental and augmented intervention for facilitating expressive language

Nearly half of all children with Autism Spectrum Disorders (ASD) are still nonverbal by 9-10 years of age despite access to current community interventions. Current treatment strategies are not sufficiently effective.

The proposed study utilizes novel intervention methods to provide skills to help nonverbal children with ASD become more effective communicators. Two approaches will be pursued. The first intervention addresses core deficits of joint attention and joint engagement in facilitating communication and language development in children with autism.

The second intervention focuses on joint engagement and the use of an augmentative and alternative communication device. These two approaches are combined with a highly novel study design that compares the sequence of the two interventions on children’s progress in communication and language.

Moreover, the research design will allow the investigators to define key factors associated with intervention success, such as the child exhibiting an initial understanding of language and oral-motor abilities.

What this means for people with autism:  

The lack of expressive language skills is a heavy burden on the child and his or her family.

The number of older children who do not develop this capacity, despite attempts at multiple interventions, is staggering.

There is thus a critical need to test the effectiveness of novel interventions for children with ASD who have not shown gains in expressive language through traditional interventions. 

Xavier Castellanos, M.D., New York University Medical College
Cathy Lord, Ph.D., New York University Medical College, Univ. of Michigan
$575,016 for 2 years

Early Development of Brain Connectivity in Autism

This research proposal will directly test a fundamental hypothesis suggesting that ASD is characterized by an over-abundance of short-distance connections and reduced long-range connections in the cerebral cortex.

This imbalance may be more or less severe depending upon functional status of the individual, but it has been difficult, if not impossible, to carry out fMRI on so-called lower-functioning individuals. The investigators have perfected a method that requires very short imaging periods (minutes) for measuring functional connectivity (defined as the degree of synchronization between distant brain regions) that they have shown to be exquisitely sensitive in detecting connectivity differences between typically developing children, adolescents and adults.

Preliminary data indicates that this team can detect autism-related differences in functional connectivity in children with high-functioning autism who are between 8-14 years of age. Here, the investigators propose a two-year cross-sectional study to examine such measures of connectivity in young children (between 36 and 60 months of age) with ASD compared to controls.

A comparative analysis across cortical regions will allow the investigators to determine whether there is a regional bias that includes frontal cortex, which is most involved in processing social information. The investigators also have included the development of analytical and imaging technologies that will be broadly applicable across imaging sites. The study thus has the opportunity to expand greatly the capacity of neuroimaging research programs around the country to include ASD as a focus of their efforts. 

What this means for people with autism: 

Our understanding of the disruption of circuit organization and function in ASD is based on imaging or electrophysiology studies performed mostly on teenage and adult subjects who are characterized as high functioning.

This new imaging approach should make it possible to extend functional neuroimaging to include very young children as well as those with severe ASD (e.g., non-verbal, disruptive behaviors), about which we have very little information. If this methodology works, it may provide a biomarker of autism functioning. 

Stan Nelson, M.D., UCLA
John Constantino, M.D., Washington University
Paul Law, M.D., MPh, Kennedy Krieger Institute
$948,789 for 1 year

Pilot project to assess web-based family recruitment for autism genetic studies

Experts agree that the need to assess large sample collections that number in the tens of thousands is fundamental to modern human genetic studies and recent studies in diabetes and breast cancer have illustrated this. Significant advances in genetic analyses of autism will require this level of ascertainment while being both rapid and affordable. Currently DNA is available on only a few thousand individuals with autism worldwide.

This proposal aims to demonstrate the feasibility of a mechanism for large-scale subject recruitment with DNA collection. The investigators propose to recruit within the Interactive Autism Network (IAN) and validate the accuracy and utility of the resulting collected samples. As the centerpiece of this pilot project, the investigators will collect DNA from 3,000 affected children in just a one-year time period, using mailer-based saliva collection kits. 

What this means for people with autism: 

The proposed studies have the potential to revolutionize the way in which subjects with autism are recruited for research studies.

By correlating fast internet-based assessments with traditional diagnostic procedures, the investigators have proposed to double the number of autism subjects with genetic samples that are currently available.

This will allow the genetic risk factors for autism to be uncovered in a much more meaningful timeframe, permitting clinical investigators to focus on development of diagnostics and targeted biological therapeutics.

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