Redefining Chiari Type I Malformation and its Impact on Brain Development

重新定义 Chiari I 型畸形及其对大脑发育的影响

• 批准号: 10629116
• 负责人: David Delmar Limbrick
• 金额: $ 155.48万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10629116
• 关键词: Address; Affect; Biological; Brain; Brain Stem; Cerebellar tonsil; Cerebellum; Clinical; Cognition; Cognitive; Complex; Data; Data Set; Development; Diagnosis; Dimensions; Environment; Etiology; Experimental Models; Expert Opinion; Functional disorder; Funding; Genetic; Genomics; Genotype; Image; Impairment; Incidental Discoveries; Individual; Injury; International; Investigation; Lead; Magnetic Resonance Imaging; Maps; Mediating; Methods; Motion; Nervous System Physiology; Neurologic Deficit; Neurologic Effect; Neurological outcome; Outcome; Pain; Participant; Pathologic; Pathology; Pathway interactions; Patient-Focused Outcomes; Patients; Pattern; Phenotype; Population; Posterior Fossa; Precision therapeutics; Quality of life; Radiology Specialty; Randomized, Controlled Trials; Research; Scheme; Scientific Advances and Accomplishments; Spinal Cord; Sum; Syringomyelia; Tonsil; Treatment outcome; Universities; Variant; Vertebral column; Washington; Work; behavioral outcome; clinical practice; cohort; deep learning; endophenotype; experience; foramen magnum; genetic variant; improved; malformation; multidimensional data; neurobehavioral; novel; pain-related disability; predictive modeling; programs; skull base; synergism; translational genomics; translational neuroscience; treatment response

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 However, current clinical practice continues to rely heavily on this oversimplified and outdated definition of CM, with most management decisions based on a single, static 2D sagittal MRI image, failing to consider the dynamic pathophysiology at the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.

项目摘要 总体：摘要 自汉斯·奇亚里（Hans Chiari）在1890年代的最初描述以来，Chiari I型畸形（CM）被定义为 小脑扁桃体下方的尾骨位移（异构）。这个定义过于简化 颅脑连接病理的复杂范围影响了1％以上的人群，几乎没有 与商业的神经系统作用有关。但是，当前的临床实践继续严重依赖这一点 CM的过度简化和过时的定义，大多数管理决定基于单个静态2D 矢状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暗示了一种过度动力的病理生理状态 CM，具有湍流的CSF流动模式，扁桃体和脑干的夸大搏动运动以及功能障碍 或小脑，脑干或脊髓损伤。 CVJ与患者的这些变化的关系 经验（疼痛和/或神经系统缺陷），认知或行为结果以及与CM相关的 色疗（SM，脊髓气穴）尚不清楚且被审查不足。 华盛顿大学的公园冰河Chiari＆Symyomyelia中心（PRCSC）成立于2011年 并已成为研究商业研究的国际领导者和充满活力的焦点。总体主题 该PRCSC计划项目提案的建议是“重新定义Chiari 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 大学要调查世界上最大，最精致的CM患者队列。四个核心 [行政（AC），临床（CC），遗传（GC）和放射学（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，Project Lead（PL）； Solnica-krezel，共同领导（CL）]； CM的功能连通性，大脑发育和结果[Dosenbach，PL; Roland and Marek，CL]； CSF介导的病理生理学和微结构损伤决定了CM的结果[Strahle，PL；歌曲，CL]； 并使用基因型 - 表型关系重新定义CM并对结果的影响[Limbrick，PL；格林伯格 lu，cl]。尽管这些核心和项目都针对独特的特定目标，但它们将产生财富 PRCSC参与者的多维数据允许凝聚力，协同和全面 检查本应用程序的总体目的。确实，PRCSC整体上比 核心和项目的总和。 总体特定目的1。确定导致CM，大脑发育和 神经功能。 总体特定目的2。确定与CM相关神经系统作用的病理生理基础。 总体特定目标3：创建一个新型的CM框架来增强治疗反应和结果。