Brain Structure and Clinical Endpoints in Myotonic Dystrophy Type 2

项目摘要 这个K23应用程序的总体目标是评估大脑结构和功能之间的关系 对强直性肌营养不良2型（DM2）的认知和运动表现的影响，从而有助于 候选人准备独立领导未来阐明DM2神经生物学的研究。虽然 肌无力是DM2的主要症状，几乎70%的患者报告认知受损是其中之一。 最致残的症状，并深深影响他们的生活质量。DM2是一种多方面的遗传性疾病， 由细胞核酸结合蛋白（CNBP）基因中的CCTG重复扩增引起，其中 RNA功能获得是主要的疾病机制。尽管DM2与肌强直性有几个区别， 1型营养不良（DM1），它们具有一些遗传和临床相似性，例如大量认知症状 和肌肉无力虽然在过去的十年中，对DM 1的脑成像研究有所增加，但相对而言， 关于DM2如何影响大脑结构和功能的知之甚少，因为DM2的脑成像研究 极其有限。这些研究的结果有相互矛盾的结果，因为样本量小，缺乏 定量分析和认知测量之间的差异。然而，大多数研究结果表明， 与对照组相比，DM 2主要影响大脑白色物质（WM），WM体积减少， 由扩散张量成像（DTI）导出的异常WM完整性。新出现的证据表明陶米斯- DM2中的剪接和缠结病理，这引起了人们对阐明tau在DM2相关疾病中的作用的兴趣。 认知障碍最近的研究强调了这种可能性， 以及阿尔茨海默病（AD）和阿尔茨海默病（AD）中皮质tau沉积和脑脊液（CSF）tau的变化。 疾病相关性痴呆（ADRD）。然而，迄今为止还没有研究评估tau在DM2中的作用。在 总之，尽管有明确的认知症状表明中枢神经系统受累，但没有研究仔细评估 CNS病理学的脑结构和液体生物标志物及其与认知和运动测量的关系 在DM2。在目标1中，我将评估脑形态测量和白色物质完整性的DTI测量，包括 各向异性分数（FA）、径向扩散率（RD）和轴向扩散率（40例DM2成人与40例年龄 和性别匹配的对照组。在目标2中，我将确定白色物质完整性（大脑）测量的关系 FA和RD）与认知和运动终点。在目标3中，我将进行一项试点概念验证研究， 表征DM 2患者CSF和血浆中的tau谱，并将这些发现与 大脑结构和认知终点的测量。拟议的综合研究、指导和 教学培训，结合维克森林大学健康的优秀研究环境 科学，将促进我的长期职业目标，成为一个独立的调查员的知识和 领导CNS表现的神经生物学研究的技能，并最终进行临床试验， 靶向治疗机制，以改善DM 2患者的结局和生活质量。

Project Summary The overall goals of this K23 application are to evaluate the relationship between brain structure and function on cognition and motor performance in myotonic dystrophy type 2 (DM2), and thereby contribute to the Candidate’s preparation to independently lead future research elucidating the neurobiology of DM2. Although muscle weakness is the key symptom in DM2, almost 70% of patients report that impaired cognition is among the most disabling symptoms, and deeply affects their quality of life. DM2, a multifaceted genetic disorder, results from a CCTG repeat expansion in the cellular nucleic acid binding protein (CNBP) gene, where the RNA gain-of-function is the main disease mechanism. Although DM2 has several distinctions from myotonic dystrophy type 1 (DM1), they share some genetic and clinical similarities, e.g. substantial cognitive symptoms and muscle weakness. While studies of brain imaging in DM1 have increased over the past decade, relatively little is known about how DM2 affects brain structure and function as brain imaging studies in DM2 are extremely limited. Results of these studies have had conflicting results because of small sample sizes, lack of quantitative analyses, and discrepancy between cognitive measures. However, most findings suggest that, compared to controls, cerebral white matter (WM) is primarily affected in DM2, with reduced in WM volume and abnormal WM integrity derived from diffusion tensor imaging (DTI). Emerging evidence has identified tau mis- splicing and tangle pathology in DM2, which has prompted interest in elucidating the role of tau in DM2-related cognitive impairment. This possibility is underscored by recent studies of relationships between WM integrity and cortical tau deposition and cerebrospinal fluid (CSF) tau in Alzheimer’s Disease (AD) and Alzheimer’s Disease Related Dementias (ADRD). Nevertheless, no study to date has evaluated the role of tau in DM2. In sum, despite clear cognitive symptoms that suggest CNS involvement, no studies have meticulously evaluated brain structure and fluid biomarkers of CNS pathology and their relationships to cognitive and motor measures in DM2. In Aim 1, I will evaluate brain morphometry and DTI measures of white matter integrity, including fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity between 40 adults with DM2 vs. 40 age- and sex-matched control. In Aim 2, I will determine relationships of measures of white matter integrity (cerebral FA and RD) with cognitive and motor endpoints. In Aim 3, I will conduct a pilot proof-of-concept study to characterize tau profiles in the CSF and plasma of patients with DM2 and associate these findings with measures of brain structure and cognitive endpoints. The proposed integrated research, mentorship, and didactic training, combined with the outstanding research environment at Wake Forest University Health Sciences, will foster my long-term career goals to become an independent investigator with the knowledge and skills to lead research on the neurobiology of CNS manifestation and ultimately clinical trials that test novel therapies targeting mechanisms to improve outcomes and quality of life in patients with DM2.