Early brain overgrowth is a recently identified, but not yet directly measured, phenomenon in autism.Direct MRI measurement of the young autistic brain comes from five studies that found brain overgrowth atmean study ages of 2.7 to 3.9 yrs. Affected brain regions mediate higher-order social, emotional, languageand cognitive functions that characterize autism. MRI studies of early brain growth in autism are absent.Indirect evidence of brain growth in autism comes from retrospective analyses of headcircumference (HC). In the first study to examine the question, we reported that HC was normal average toslightly smaller than normal at birth in those who later manifested autism, but by about 12 months HC wasabnormally large. Inferring brain growth rates from age-related changes in HC and placing that with the fiveMRI brain size studies of 2 to 4 year olds led us to the hypothesis that autism may involve a brief and agedelimitedperiod of abnormal brain overgrowth during the first two years of life.According to the only two existent prospective studies of autism, 12 months is also approximately thefirst age at which autistic behavioral abnormalities first become detectable. The formation of neural circuitryis at its most exuberant and vulnerable stage during this period of development. Aberrant connectivity andneural dysfunction resulting from disruptions to this process may be key to the development of autisticbehaviors. Thus, the first years of life in autism offer a unique chance to track the simultaneous emergingexpression of the autistic anatomical and clinical phenotype and establish their relationship to each other andto underlying causal mechanisms, such as genes and genetic pathways that affect brain growth.We will identify early brain growth biomarkers in ASD by longitudinally MRI scanning infants at-riskfor ASD, infants at-risk for developmental delay and typical infants at 12 and 24 months. We will obtainregion-specific measures of volume, area, cortical thickness, fractional anisotropy and apparent diffusivitycoefficient and developmental change values. Detailed anatomic maps of each region will be derived foreach infant at each age. At age 36 months, a final best estimate diagnostic evaluation will identify which atriskinfants are ASD, DD or other. MRI results from these ASD and DD infants and typical infants will bestatistically compared and early ASD brain growth abnormalities identified. Anatomical measures will beidentified that characterize and predict the early developmental clinical phenotype of ASD that Cores B andC in collaboration with the Integrated Biostatistics Core D will identify. We will work with Project 4 and theIntegrated Biostatistics Core D to use the brain growth biomarkers to discover overgrowth susceptibilitygenes and pathways. With Core D, we will identify separate clusters of distinctly different brainmaldevelopment phenotypes among the ASD infants.
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