Mechanisms of Gait and Balance Impairment in Progressive Supranuclear Palsy

项目总结/摘要 进行性核上性麻痹（PSP）是一种致命的、进行性的、不可治愈的神经退行性tau蛋白病。Falls 由步态和平衡障碍引起的疾病是该病的主要特征， 综合征目前，这些异常的检测主要依赖于主观的临床检查， 鳞片目前还没有标准化的方法来量化PSP中步态和平衡障碍的具体特征。 诊断和预后测试侧重于患者相关的结果，如步态相关的残疾， needed.运动分析技术可用于步态和平衡变量的客观定性。这 为开发以患者为中心的诊断工具提供了机会，这些工具可以测量步态障碍的特征， 及其对福尔斯风险的影响。基于摄像机的视频运动捕捉利用多个高频摄像机 在良好校准的受控环境中生成人体运动的三维模型， 平衡这被认为是最准确和可靠的运动分析方法。我们的项目将利用 基于实验室的运动捕捉，以确定最能表征PSP理查森综合征的步态指标， PSP-皮质和PSP-皮质下综合征和区分PSP从正常对照。然而，经认可的 运动分析实验室不容易进入，并且需要复杂的通常昂贵的设置。身体穿戴 运动传感装置提供了一种可行的替代方案。它们具有成本效益，便携式，易于在门诊使用 设置.然而，必须确定这些器械在特定患者中的可靠性和准确性 人群，并评估所采集数据的临床意义。因此，在本项目中，我们将采用 身体佩戴的运动感测设备或惯性监测单元（IMU），以检测步态和平衡度量， 表征PSP。然后将来自IMU的数据与运动分析实验室进行比较，以确定其 精度步态指标有可能作为PSP中以患者为中心的结局指标。在这个项目中 我们也将使用这些变量来分析步态和平衡的神经生物学机制 PSP受损。我们将识别的步态和平衡指标与体积磁共振成像相关联。 磁共振成像（MRI），扩散MRI（dMRI）和纤维束成像，以确定皮质破坏的模式 和皮层下运动控制系统。性别作为一个生物学上重要的变量的影响将是 评估。年龄将作为协变量，以识别与疾病状态特异性相关的步态异常， 而不是继发于正常老化。该研究项目的成果将有助于患者的发展 中心结局指标，临床异质性评估和步态机制的理解 PSP综合征的损害。未来的方向将包括纵向评估和比较 分析相关神经退行性疾病，以推进以患者为中心的诊断和开发 临床试验的结果测量。

PROJECT SUMMARY/ABSTRACT Progressive supranuclear palsy (PSP) is a fatal, progressive, incurable neurodegenerative tauopathy. Falls resulting from gait and balance impairments are a cardinal feature of the disease and occur in all PSP syndromes. Currently, detection of these abnormalities relies on largely subjective clinical examination and scales. There are no standardized ways to quantify specific features of gait and balance impairments in PSP. Diagnostic, and prognostic tests focusing on patient relevant outcomes such as gait related disability are needed. Motion analysis technology can be used for objective qualification of gait and balance variables. This offers an opportunity to develop patient-centric diagnostic tools that can measure features of gait impairment and its impact on risk for falls. Laboratory-based video motion capture utilizes multiple high frequency cameras in a well calibrated controlled environment to generate a three-dimensional model of human locomotion and balance. This is considered the most accurate and reliable method of motion analysis. Our project will utilize laboratory-based motion capture to identify gait metrics that best characterize PSP Richardson syndrome, PSP-cortical and PSP-subcortical syndromes and distinguish PSP from normal controls. However, accredited motion analysis labs are not readily accessible, and require an elaborate usually expensive set-up. Body-worn motion-sensing devices offer a feasible alternative. They are cost-effective, portable, easy to use in ambulatory settings. However, it is essential to establish reliability and accuracy of these devices in specific patient populations and assess clinical significance of the data captured. Therefore, in this project we will employ a body-worn motion sensing device or inertial monitoring unit (IMU) to detect gait and balance metrics that best characterize PSP. The data from the IMU will then be compared to the motion analysis lab to establish its accuracy. Gait metrics have the potential to serve as patient-centric outcome measures in PSP. In this project we will also use these variables to analyze neurobiological mechanisms underlying gait and balance impairment in PSP. We will correlate the identified gait and balance metrics with volumetric magnetic resonance imaging (MRI), diffusion MRI (dMRI) and tractography to determine patterns of disruption of cortical and subcortical motor control systems in PSP. The effect of sex as a biologically significant variable will be assessed. Age will be a covariate to identify gait abnormalities that are specifically related to disease state and not secondary to normal aging. The outcomes of this research project will contribute to development of patient centric outcome measures, assessment of clinical heterogeneity and understanding of mechanisms of gait impairment in PSP syndromes. Future directions will include longitudinal assessment and comparative analyses across related neurodegenerative diseases to advance diagnosis and development of patient centric outcome measures for clinical trials.