Gross morphological correlates to the minicolumnopathy of autism

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DESCRIPTION (provided by applicant): The minicolumn is a basic anatomical and physiological element of the mammalian cerebral cortex, comprising a linear array of pyramidal cell bodies, their projections, and accompanying GABAergic interneurons. Postmortem studies of the organization of pyramidal cell arrays in autism have revealed that minicolumns in the brains of autistic patients are narrower. Since the minicolumn re-iterates itself millions of times throughout the brain, variations in the total number and width of minicolumns may result in macroscopic changes to the brain's surface area, folding (gyrification), and white matter pathways linking regional networks of minicolumns. In effect, data derived from comparative anatomy studies indicates that minicolumnar findings, if generalized, have specific gross correlates that can be detected by MRI. These changes include alterations in the gyral window, gray/white matter ratio, parcellation of the white matter, and size of the corpus callosum. This grant proposes studying a unique series of cases (n = 58) derived from the Autism Tissue Program (ATP). All of the cases included in this study had clinical documentation and a postmortem MRI. Autism was diagnosed according to DSM-IV-TR and ADI-R criteria. There are three specific aims to our study: 1) To quantify and compare the radial structure of dendritic bundles in the cerebral cortex of postmortem autistic patients and controls, 2) To determine the correlation between minicolumnar structure defined by fiber bundles and white matter distribution in the brains of postmortem autistic patients and controls, and 3) To perform a cluster analysis of autism diagnostic criteria and morphometric measurements. Specific aim 3 is an exploratory study that will attempt to provide construct validity to a current diagnostic scheme (ADI-R) by correlating clinical parameters to obtained neuropathological/neuroimaging data. All of the aims are in-keeping with the research objectives of the applied request for applications (RFA-MH-09-170). In order to achieve our specific aims the proposed study will correlate anthropometric indices (MRI) to specific minicolumnar parameters. Postmortem data will be derived from the analysis of apical dendritic bundles in nine cortical areas that display varying degrees of cytoarchitectural differentiation: paralimbic, high- order (hetermodal) association, modality-specific (unimodal) association, and idiotypic areas (primary sensory/motor cortices) (BA 4, 9, 10, 17, 21, 22, 33, 39, and 40). Other areas, i.e., corticoid and all cortical formations, were not included in our sampling scheme due to their lack of minicolumnar organization. The analysis of specific minicolumnar compartments will allow us to screen a series of anatomical elements incriminated in previous studies, i.e., minicolumnar narrowing most prominently in the peripheral neuropil space. Preliminary findings suggest: 1) high predictive ability between macro- and microscopic parameters, and 2) a high degree of diagnostic (autism) selectivity when combining the different anthropometric indices espoused in this grant proposal. PUBLIC HEALTH RELEVANCE: This project attempts to establish a correlation between autopsy and neuroimaging findings in autism. The intent is to develop markers of the condition that can be detected while the patient is alive. Another innovative aspect of the proposal is an attempt to validate current diagnostic screening techniques against autopsy findings.