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 However, current clinical practice continues to rely heavily on this oversimplified and outdated definition of CM, with most management decisions based on a single, static 2D sagittal MRI image, failing to consider the dynamic pathophysiology at the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

项目总结 总体：摘要 自19世纪90年代Hans Chiari首次描述以来，Chiari I型畸形(CM)一直被定义为 枕大孔下方小脑扁桃体尾侧移位(异位)。这个定义过于简单化了 颅颈交界处复杂的病理范围影响到超过1%的人口，几乎没有 与CM的神经效应的相关性。然而，目前的临床实践仍然严重依赖这一点。 CM的定义过于简单和过时，大多数管理决策都基于单一的静态2D 矢状位MRI图像，未能考虑小脑、脑干、 和脊髓。我们小组和其他人的研究表明， Cm，伴有湍流的脑脊液流动模式，扁桃体和脑干的过度搏动性运动，以及功能障碍 或小脑、脑干或脊髓损伤。CVJ的这些变化与患者的关系 体验(疼痛和/或神经缺陷)、认知或行为结果以及CM相关 脊髓空洞症(SM，脊髓空洞)，目前仍不清楚，也未被充分研究。 华盛顿大学帕克-里夫斯·恰里和脊髓空洞症中心成立于2011年 并已成为中医药研究的国际领先者和充满活力的焦点。最重要的主题 PRCSC计划项目建议书中的一项是“重新定义Chiari I型畸形及其对 神经后果。“这项提议将利用华盛顿的关键优势和科学进步。 大学调查世界上最大和最精细的CM患者队列。四核 [行政(AC)、临床(CC)、遗传学(GC)和放射学(RC)核心]将支持4个项目：遗传学 CM的基础及其对大脑发育的影响[Haller，项目领导(PL)；Solnica-Krezel，共同领导(CL)]； 功能连接、脑发育和CM的结果[Dosenbach，PL；Roland和Marek，CL]； 脑脊液介导的病理生理学和微结构损伤决定CM的预后[Strahle，PL；Song，CL]； 以及使用基因-表型关系和对结果的影响来重新定义CM[Limrick，PL；Greenberg 和Lu，CL]。尽管这些核心和项目都针对独特的具体目标，但它们将创造财富 来自PRCSC参与者的多维数据，以实现凝聚力、协同性和全面性 审查这项申请的总体目标。事实上，PRCSC作为一个整体，远远大于 其核心和项目的总和。 总体特定目标1.确定影响CM、大脑发育和 神经功能。 总体特定目标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，以提高治疗反应和结果。