Establishing a Novel Neural Tissue Deformation Biomarker for Type 1 Chiari Malformation

项目摘要 未经治疗的1型基亚里畸形（CM 1）是一种毁灭性的神经系统疾病，可以通过 高风险和昂贵的脑部手术。由于决定手术往往是基于共同的症状，如 作为头痛，沿着小脑扁桃体位置的单一成像测量，其通常被认为是 由于医疗服务不足，人们对治疗不足，特别是过度治疗的关注很高。CM1公众迫切需要一个 更好地反映CM1病理生理学的生物标志物，使医生能够更准确地选择手术。 这项建议旨在用一种新的方法取代小脑扁桃体下降的简单CM1诊断方法。 基于MRI的生物标志物，可量化心脏固有诱导的拉伸和压缩（变形）， 大脑和脊髓我们的中心假设是，在特定的动态变形的量化， 中枢神经系统组织区域将是一个生物标志物，以帮助适当选择人与>5毫米 扁桃体下降进行手术治疗。不可能量化神经组织应力或压力 非侵入性地。然而，组织变形可以用相位对比（PC）MRI或MRI无创地测量。 受激回波位移编码（DENSE）。我们的初步数据和出版物显示， CM 1中神经组织变形评估重要性的证据和确认的DENSE序列 优化和测量的可靠性。此外，我们研究团队的所有成员都有 获得了多项专注于CM1的研究赠款，并在多个资助的CM1项目中合作。 为了检验我们的假设，在目标1中，我们将比较术前有症状的CM1患者（N=20）与 使用动态变形参数（整体运动、压缩、拉伸和剪切）的健康对照（N=20） 使用PC MRI和DENSE在脊髓、脑干和小脑扁桃体处获得。这一目标将 建立动态变形参数作为有症状的CM1的生物标志物。在目标2中，我们将比较 有症状的CM1患者（N=20）与扁桃体>6 mm的无症状受试者的神经组织变形 下降至枕骨大孔以下（N=20）。这一目标将建立动态变形作为生物标志物， 减轻CM1假阳性诊断。在目标3中，我们将确定CM1的手术治疗如何改变 神经组织变形及其与症状改善的相关性。这一目标将有助于理解 变形与手术成功的关系我们的长期目标是开发先进的磁共振成像技术， 分析技术，形成一个CM1生物力学分析工具集，可用于临床和应用于 多中心研究，将有助于早期发现，更精确的诊断和临床管理的CM1。

Project Summary Untreated Type 1 Chiari malformation (CM1) is a devastating neurological disorder that can be treated by a high risk and costly brain operation. Since the decision to operate is often based on common symptoms, such as headache, along with a single imaging measure of cerebellar tonsil position that is commonly recognized as inadequate, the concern for under- and especially over-treatment is high. The CM1 public critically needs a biomarker that better reflects CM1 pathophysiology, allowing physicians a more accurate surgical selection. This proposal seeks to replace the simplistic CM1 diagnostic measure of cerebellar tonsil descent with a novel MRI-based biomarker that quantifies intrinsic cardiac-induced stretching and compression (deformation) of the brain and spinal cord. Our central hypothesis is that quantification of dynamic deformation within specific central nervous system tissue regions will be a biomarker to help appropriately select people with >5 mm tonsillar descent for surgical treatment. It is not possible to quantify neural tissue stress or pressure noninvasively. However, tissue deformation can be measured noninvasively with phase contrast (PC) MRI or displacement encoding with stimulated echoes (DENSE). Our preliminary data and publications show strong evidence for the importance of neural tissue deformation assessment in CM1 and confirmed DENSE sequence optimization and measurement reliability in the brain. Additionally, all members of our research team have received multiple research grants focused on CM1 and worked together in multiple funded CM1 projects. To test our hypothesis, in Aim 1, we will compare symptomatic CM1 patients, prior to surgery (N=20), to healthy controls (N=20) using dynamic deformation parameters (bulk motion, compression, tension, and shear) obtained at the spinal cord, brain stem, and cerebellar tonsils using PC MRI and DENSE. This aim will establish dynamic deformation parameters as a biomarker for symptomatic CM1. In Aim 2, we will compare neural tissue deformation in symptomatic CM1 patients (N=20) to asymptomatic subjects with >6 mm tonsillar descent below the foramen magnum (N=20). This aim will establish dynamic deformation as a biomarker that mitigates CM1 false-positive diagnosis. In Aim 3, we will determine how surgical treatment of CM1 alters neural tissue deformation and its correlation with symptom improvement. This aim will allow understanding of how deformation relates to surgical success. Our long-term goal is to develop advanced MR imaging and analysis techniques to form a CM1 biomechanics analysis tool-set that can be used clinically and applied in a multicenter study that will aid early detection, more precise diagnosis, and clinical management of CM1.