Gross morphological correlates to the minicolumnopathy of autism

总体形态学与自闭症的微小柱状病相关

• 批准号: 7940986
• 负责人: Manuel F Casanova
• 金额: $ 25.9万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7940986
• 关键词: Accounting; Adrenal Cortex Hormones; Affect; Age; Algorithms; Apical; Applications Grants; Area; Autistic Disorder; Autopsy; Award; Behavior; Body Image; Body Size; Brain; Case Series; Celloidin; Cells; Cerebral cortex; Clinical; Cluster Analysis; Code; Cognitive; Comparative Anatomy; Controlled Study; Corpus Callosum; Data; Development; Diagnosis; Diagnostic; Disease; Documentation; Electroencephalography; Elements; Evolution; Fiber; Grant; Gray unit of radiation dose; Homologous Gene; Image; Interneurons; Interview; Left; Link; Magnetic Resonance Imaging; Measurement; Measures; Microscopic; Modality; Morphologic artifacts; Morphology; Motor Cortex; Neocortex; Neurons; Neuropil; Pathology; Pathway interactions; Patients; Peripheral; Physiological; Primates; Process; Pyramidal Cells; Radial; Reporting; Request for Applications; Research; Research Personnel; Rodent; Sampling; Scheme; Screening procedure; Sensory; Series; Severities; Shapes; Specimen; Staining method; Stains; Structure; Surface; Symptoms; Synapses; Syndrome; Techniques; Testing; Time; Tissues; Trees; Variant; Width; Wit; area striata; base; brain size; comparative; endophenotype; falls; imaging modality; in vivo; indexing; innovation; morphometry; neuroimaging; neuronal cell body; programs; public health relevance; sex; white matter

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.

描述（由申请人提供）：微柱是哺乳动物大脑皮层的基本解剖学和生理学元件，包括锥体细胞体、其突起和伴随的GABA能中间神经元的线性阵列。对自闭症患者的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更窄。由于微柱在整个大脑中重复自身数百万次，微柱的总数和宽度的变化可能导致大脑表面积、折叠（回转）和连接微柱的区域网络的白色物质通路的宏观变化。实际上，来自比较解剖学研究的数据表明，如果是广义的，微柱表现具有特定的大体相关性，可以通过MRI检测到。这些改变包括脑回窗、灰/白色物质比例、白色物质的分隔和胼胝体大小的改变。 这项资助计划研究来自自闭症组织计划（ATP）的一系列独特的病例（n = 58）。本研究中纳入的所有病例均有临床记录和尸检MRI。根据DSM-IV-TR和ADI-R标准诊断孤独症。我们的研究有三个具体目标：1）量化和比较死后自闭症患者和对照者大脑皮层中树突束的放射状结构，2）确定死后自闭症患者和对照者大脑中由纤维束限定的微柱结构与白色物质分布之间的相关性，3）对孤独症的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，将尝试通过将临床参数与获得的神经病理学/神经影像学数据相关联，为当前诊断方案（ADI-R）提供结构效度。所有这些目标都符合申请请求（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minicolumnar参数。尸检数据将来源于对9个皮质区中顶端树突束的分析，这些皮质区显示出不同程度的细胞结构分化：边缘区、高阶（异模态）关联、模态特异性（单峰）关联和独特型区域（初级感觉/运动皮质）（BA 4、9、10、17、21、22、33、39和40）。其他领域，即，皮质激素和所有皮质形成，由于缺乏微柱组织，未包括在我们的取样方案中。对特定微柱间室的分析将使我们能够筛选出一系列在以前的研究中涉及的解剖学要素，即，微柱狭窄在周围神经间隙中最显著。初步调查结果表明：1）宏观和微观参数之间的高预测能力，以及2）当结合本资助提案中所支持的不同人体测量指标时，高度的诊断（自闭症）选择性。 公共卫生相关性：该项目试图建立自闭症尸检和神经影像学发现之间的相关性。其目的是开发可以在患者活着时检测到的疾病标志物。该提案的另一个创新方面是试图根据尸检结果验证目前的诊断筛查技术。

项目成果

The Developmental Gene Hypothesis for Punctuated Equilibrium: Combined Roles of Developmental Regulatory Genes and Transposable Elements.

间断平衡的发育基因假说：发育调节基因和转座元件的联合作用。

• DOI: 10.1002/bies.201900173
• 发表时间: 2020
• 期刊: BioEssays : news and reviews in molecular, cellular and developmental biology
• 作者: Casanova,EmilyL;Konkel,MiriamK
• 通讯作者: Konkel,MiriamK

A Cohort Study Comparing Women with Autism Spectrum Disorder with and without Generalized Joint Hypermobility.

• DOI: 10.3390/bs8030035
• 发表时间: 2018-03-17
• 期刊: Behavioral sciences (Basel, Switzerland)
• 作者: Casanova EL;Sharp JL;Edelson SM;Kelly DP;Casanova MF
• 通讯作者: Casanova MF

Above genetics: lessons from cerebral development in autism.

• DOI: 10.2478/s13380-011-0016-3
• 发表时间: 2011-06-01
• 期刊: Translational neuroscience
• 影响因子: 2.1
• 作者: Williams EL;Casanova MF
• 通讯作者: Casanova MF

Focal cortical dysplasias in autism spectrum disorders.

• DOI: 10.1186/2051-5960-1-67
• 发表时间: 2013-10-11
• 期刊: Acta neuropathologica communications
• 影响因子: 7.1
• 作者: Casanova MF;El-Baz AS;Kamat SS;Dombroski BA;Khalifa F;Elnakib A;Soliman A;Allison-McNutt A;Switala AE
• 通讯作者: Switala AE

Genetics studies indicate that neural induction and early neuronal maturation are disturbed in autism.

• DOI: 10.3389/fncel.2014.00397
• 发表时间: 2014
• 期刊: Frontiers in cellular neuroscience
• 影响因子: 5.3
• 作者: Casanova EL;Casanova MF
• 通讯作者: Casanova MF