Gross morphological correlates to the minicolumnopathy of autism

描述(申请人提供)：小柱是哺乳动物大脑皮层的基本解剖和生理成分，由锥体细胞体、它们的投射和伴随的GABA能中间神经元组成的线性阵列。对自闭症患者锥体细胞阵列组织的尸检研究表明，自闭症患者大脑中的微柱较窄。由于微柱在整个大脑中重复数百万次，所以微柱的总数和宽度的变化可能会导致大脑表面积、折叠(回转)和连接区域微柱网络的白质通路的宏观变化。实际上，来自比较解剖学研究的数据表明，如果广义的话，微小的脊柱病变具有特定的大体相关性，可以通过MRI检测到。这些变化包括脑回窗口、灰质/白质比、白质分隔和胼胝体大小的改变。这项资助建议研究一系列来自自闭症组织计划(ATP)的独特病例(n=58)。这项研究中的所有病例都有临床文献和尸检核磁共振检查。孤独症的诊断依据DSM-IV-TR和ADI-R标准。本研究有三个具体目的：1)量化和比较自闭症患者和对照组大脑皮层树突束的放射状结构；2)确定自闭症患者和对照组死后脑白质分布与由纤维束定义的微柱结构之间的相关性；3)对自闭症诊断标准和形态测量进行聚类分析。具体目标3是一项探索性研究，试图通过将临床参数与获得的神经病理/神经成像数据相关联，为当前的诊断方案(ADI-R)提供结构效度。所有这些目标都符合申请申请书(RFA-MH-09-170)的研究目标。为了实现我们的特定目标，拟议的研究将人体测量指数(MRI)与特定的微柱参数相关联。尸检数据将来自于对9个皮质区域顶端树突束的分析，这些区域显示出不同程度的细胞结构分化：边缘旁、高阶(异型)联结、形态特有(单峰)联结和独特型区(初级感觉/运动皮质)(BA 4、9、10、17、21、22、33、39和40)。其他区域，即皮质和所有皮质结构，没有包括在我们的抽样方案中，因为它们缺乏细小的柱状结构。对特定的小柱间隔的分析将使我们能够筛选出先前研究中涉及的一系列解剖学因素，即小柱狭窄最明显地位于周围神经束间隙。初步结果表明：1)宏观和微观参数之间的高度预测能力，以及2)当结合本拨款提案中支持的不同人体测量指数时，高度的诊断(自闭症)选择性。 公共卫生相关性：该项目试图在自闭症的尸检和神经成像结果之间建立关联。其目的是开发可以在患者活着时检测到的病情标记。该提案的另一个创新方面是试图对照尸检结果验证当前的诊断筛查技术。

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.