Redefining Chiari Type I Malformation and its Impact on Brain Development

项目摘要 总体：摘要 自19世纪90年代Hans基亚里首次描述以来，基亚里I型畸形（CM）被定义为 小脑扁桃体在枕骨大孔下方的尾部移位（异位）。这个定义过于简单化了 颅颈交界处病变的复杂范围影响超过1%的人群， 与CM的神经效应相关。然而，当前的临床实践仍然严重依赖于此 过于简化和过时的CM定义，大多数管理决策都基于单一的静态2D 矢状面MRI图像，未能考虑小脑，脑干， 和脊髓。我们小组和其他人的调查表明， CM，伴有脑脊液湍流模式，扁桃体和脑干的搏动运动过度，功能障碍 或损伤小脑脑干或脊髓。CVJ的这些变化与患者的关系 经验（疼痛和/或神经功能缺损），认知或行为结果，以及CM相关 脊髓空洞症（SM，脊髓空洞），仍然不清楚，研究不足。 华盛顿大学的Park-Reeves基亚里和脊髓空洞症中心（PRCSC）成立于2011年 并已成为国际领先的和充满活力的焦点研究到CM。总主题 该PRCSC计划项目建议书的第一部分是“重新定义基亚里I型畸形及其对 神经学结果”。该提案将利用华盛顿的关键优势和科学进步 该大学调查了世界上最大和最精细的CM患者队列。四个核 [行政（AC）、临床（CC）、遗传（GC）和放射（RC）核心]将支持4个项目：遗传 CM的基础和对大脑发育的影响[Haller，项目负责人（PL）; Solnica-Krezel，共同负责人（CL）]; CM的功能连接、大脑发育和结局[Dosenbach，PL;罗兰和Marek，CL]; CSF介导的病理生理学和微结构损伤决定CM的结局[Strahle，PL; Song，CL]; 和使用基因型-表型关系和对结果的影响重新定义CM [Limbrick，PL; Greenberg 和Lu，CL]。虽然这些核心和项目都有其独特的具体目标，但它们将产生财富。 从PRCSC参与者的多维数据，以允许一个连贯的，协同的，全面的 审查本申请的总体目标。事实上，中国证监会作为一个整体， 其核心和项目的总和。 具体目标1。确定导致CM的遗传因素，大脑发育， 神经功能 具体目标2。确定CM相关神经效应的病理生理学基础。 总体具体目标3：创建一个新的CM框架，以增强治疗反应和结局。

PROJECT SUMMARY Overall: Abstract Since its original description by Hans Chiari in the 1890s, Chiari type I malformation (CM) has been defined as caudal displacement (ectopia) of the cerebellar tonsils below the foramen magnum. This definition oversimplifies the complex range of craniovertebral junction pathology affecting more than 1% of the population and has little relevance to the neurological effects of CM. However, current clinical practice continues to rely heavily on this oversimplified and outdated definition of CM, with most management decisions based on a single, static 2D sagittal MRI image, failing to consider the dynamic pathophysiology at the interface of the cerebellum, brainstem, and spinal cord. Investigations from our group and others implicate a hyperdynamic pathophysiological state in CM, with turbulent CSF flow patterns, exaggerated pulsatile motion of the tonsils and brainstem, and dysfunction or injury to the cerebellum, brainstem, or spinal cord. The relationship of these changes at the CVJ to patient experience (pain and/or neurological deficits), cognitive or behavioral outcome, and CM-associated syringomyelia (SM, spinal cord cavitation), remains unclear and under-investigated. The Park-Reeves Chiari & Syringomyelia Center (PRCSC) at Washington University was established in 2011 and has become the international leader and vibrant focal point for research into CM. The Overarching Theme of this PRCSC Program Project Proposal is “Redefining Chiari Type I Malformation and its Impact on Neurological Outcome.” This proposal will leverage key strengths and scientific advances at Washington University to investigate the largest and most refined cohort of CM patients in the world. Four Cores [Administrative (AC), Clinical (CC), Genetic (GC), and Radiology (RC) Cores] will support 4 Projects: Genetic Underpinnings of CM and Effect on Brain Development [Haller, Project Lead (PL); Solnica-Krezel, Co-Lead (CL)]; Functional Connectivity, Brain Development, and Outcomes in CM [Dosenbach, PL; Roland and Marek, CL]; CSF-Mediated Pathophysiology and Microstructural Injury Determines Outcomes in CM [Strahle, PL; Song, CL]; and Redefining CM Using Genotype-Phenotype Relationships and Impact on Outcome [Limbrick, PL; Greenberg and Lu, CL]. Although these Cores and Projects each address unique Specific Aims, they will generate a wealth of multidimensional data from PRCSC participants to permit a cohesive, synergistic, and comprehensive examination of the overarching Aims of this application. Indeed, PRCSC as a whole is much greater than the sum of its Cores and Projects. Overall Specific Aim 1. Determine the genetic factors contributing to CM, brain development, and neurological function. Overall Specific Aim 2. Determine the pathophysiological basis for CM-related neurological effects. Overall Specific Aim 3: Create a novel CM framework to enhance treatment response and outcomes.