Optimizing Phenogenotypic and Neuromodulation Predictors in Deep Brain Stimulation Surgery for Isolated Dystonia

项目摘要/摘要 肌张力障碍是一种多动症，其特征是反复的拉动动作和异常 姿势。原发性(孤立性)肌张力障碍是第三种最常见的运动障碍，通常是进行性和 正在禁用。由于目前还没有治愈的方法，因此需要对这种疾病进行适当的治疗。可获得的药物 治疗只是有症状的，经常伴随着症状的不完全缓解和 严重的副作用。脑深部刺激(DBS)手术可以改变对症治疗的生活 有些人患有肌张力障碍，但对其他人几乎没有好处。对DBS的良好反应的决定因素 都是未知的。DBS后获益较少可能是由于遗传病因和变异性 肌张力障碍的临床表现。该项目将解决这些知识差距，重点是确定 这些因素与肌张力障碍患者令人满意的临床结果相关。 我将利用一个独特的群体来调查这些问题： 巴赫曼-施特劳斯肌无力和帕金森基金会(BSDPF)卓越中心联盟 来自四个美国中心的DBS肌张力障碍患者数据存储库，其共同目标是共享临床、 遗传学、运动生理学和成像数据。此数据集包括我们的DBS治疗肌张力障碍的良好特征 加州大学旧金山分校的人口，是世界上最大的肌张力障碍手术治疗人群之一。这 该项目的重点是了解肌张力障碍的遗传原因和表型如何预测运动益处。在 更多的联盟人口，来自四个经验丰富的星展中心的所有星展病例将进行筛查，以确定是否已知 将比较突变和遗传修饰物，以及纵向手术运动和残疾分级量表 在不同的突变和表型之间，目的是确定相关的特定特征 有了最大的进步。这项研究的结果将使我们能够了解 强调对DBS的响应，这是设计最有效的个性化信息的关键 肌张力障碍的治疗。 这个建议的研究项目与我成为一名神经流行病学医生的长期职业目标非常契合。 擅长开发针对肌张力障碍和其他运动障碍的个性化疗法。我在中国的培训计划 该奖项包括课程作业和广泛的指导教程，以进一步发展我的流行病学 研究技能和临床试验方法，并增加我对DBS机制和人类的知识 遗传学。从这个奖项中获得的知识和培训将使我成为这一领域的领导者 不断发展的个性化精确医学领域，并解决肌张力障碍的相关未得到满足的需求。

PROJECT SUMMARY/ABSTRACT Dystonia is a hyperkinetic movement disorder characterized by repetitive pulling movements and abnormal postures. Primary (isolated) dystonia is the third most common movement disorder, is often progressive and disabling. Adequate therapies for this illness are needed as there is not yet a cure. The available drug treatments are only symptomatic in nature, frequently associated with incomplete symptom relief and significant side effects. Deep brain stimulation (DBS) surgery can be a life altering symptomatic treatment for some persons with dystonia, but in others there is little benefit. The determinants of a good response to DBS are not known. Poor benefit following DBS may be due to heterogeneity in the genetic etiology and variability in the clinical presentation of dystonia. This project will address these knowledge gaps, focusing on identifying those factors associated with satisfactory clinical outcomes in dystonia. I will take advantage of a unique population to investigate these questions: the data repository of the Bachmann-Strauss Dystonia and Parkinson Foundation (BSDPF) Centers of Excellence Consortium, a repository of data on DBS dystonia patients from four U.S. centers, with the common goal of sharing clinical, genetic, motor physiology and imaging data. This dataset includes our well-characterized DBS treated dystonia population at UCSF, one of the largest populations of surgically-treated people with dystonia world wide. This project focuses on understanding how genetic causes and phenotype of dystonia predict motoric benefit. In the larger coalition population, all DBS cases from four experienced DBS centers will be screened for known mutations and genetic modifiers, and longitudinal surgical motor and disability rating scales will be compared among different mutations and phenotypes with the goal of determination of specific characteristics associated with greatest improvement. The results from this study will allow us to understand important factors that underline responsiveness to DBS, information that is critical to designing the most effective personalized treatments in dystonia. This proposed research project fits nicely with my long-term career goal of becoming a neuroepidemiology expert in developing personalized therapeutics for dystonia and other movement disorders. My training plan in this award includes course work and extensive mentored tutorials to further develop my epidemiological research skills and clinical trial methodology, and increase my knowledge of DBS mechanisms and human genetics. The knowledge and training acquired from this award will allow me to emerge as a leader in this evolving field of individualized precision medicine and address relevant unmet needs in dystonia.