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

项目总结/摘要 肌张力障碍是一种多动性运动障碍，其特征是重复的牵拉运动和异常的 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，通常是进行性的， 禁用。这种疾病需要适当的治疗，因为目前还没有治愈的方法。可用的药物 治疗本质上仅是对症的，通常与不完全的症状缓解相关， 严重的副作用。脑深部电刺激（DBS）手术可能是一种改变生活的对症治疗， 有些人与肌张力障碍，但在其他人几乎没有好处。DBS良好反应的决定因素 不知道。DBS后获益不佳可能是由于遗传病因学的异质性和 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的满意临床结局相关。 我将利用一个独特的群体来研究这些问题： Bachmann-Strauss肌张力障碍和帕金森基金会（BSDPF）卓越中心联盟， 来自美国四个中心的DBS肌张力障碍患者数据库，其共同目标是共享临床， 遗传学、运动生理学和成像数据。该数据集包括我们的特征良好的DBS治疗肌张力障碍 UCSF是世界上最大的肌张力障碍患者群体之一。这 项目的重点是了解遗传原因和肌张力障碍的表型如何预测运动的好处。在 更大的联盟人群，来自四个有经验的DBS中心的所有DBS病例将进行已知的 突变和遗传修饰，纵向手术运动和残疾评级量表将进行比较 在不同的突变和表型之间，目的是确定相关的特定特征， 最大的改善。这项研究的结果将使我们能够了解重要因素， 强调对DBS的响应，这些信息对于设计最有效的个性化 肌张力障碍的治疗 这个研究项目很好地符合我的长期职业目标，成为一个神经流行病学。 专家在开发个性化治疗肌张力障碍和其他运动障碍。我的训练计划 该奖项包括课程工作和广泛的指导教程，以进一步发展我的流行病学 研究技能和临床试验方法，并增加我的DBS机制和人类的知识 遗传学从这个奖项获得的知识和培训将使我成为这方面的领导者。 不断发展的个性化精准医疗领域，并解决肌张力障碍相关未满足的需求。

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.