Brain Structure and Clinical Endpoints in Myotonic Dystrophy Type 2

项目摘要 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)患者的认知和运动表现的影响 候选人准备独立领导未来阐明DM2神经生物学的研究。虽然 肌肉无力是DM2的主要症状，几乎70%的患者报告说认知障碍是 最具致残性的症状，并深刻影响他们的生活质量。DM2，一种多方面的遗传病， 由细胞核酸结合蛋白(CNBP)基因的CCTG重复扩增所致，其中 RNA功能增强是该病的主要发病机制。尽管DM2与强直性肌强直有几个区别 1型营养不良症(DM1)，它们有一些遗传和临床相似之处，例如实质性的认知症状 和肌肉无力。虽然在过去的十年中，对DM1的大脑成像的研究有所增加，但相对 与DM2的脑成像研究一样，人们对DM2如何影响大脑结构和功能知之甚少 非常有限。这些研究的结果相互矛盾，因为样本量小，缺乏 量化分析，以及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，DM2主要影响脑白质(WM)，WM体积减少， 弥散张量成像(DTI)显示异常的WM完整性。新出现的证据已经确定了tau的错误- DM2中的剪接和缠结病理，这引起了人们对阐明tau在DM2相关中的作用的兴趣 认知障碍。最近对工作记忆完整性之间关系的研究强调了这种可能性 阿尔茨海默病(AD)和阿尔茨海默病(AD)的皮质tau沉积和脑脊液tau 疾病相关性痴呆(ADRD)。然而，到目前为止，还没有研究评估tau在DM2中的作用。在……里面 总而言之，尽管明显的认知症状表明中枢神经系统受累，但还没有研究仔细评估 中枢神经系统病理的脑结构和流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，我将评估大脑形态测量和脑白质完整性的DTI测量，包括 40名患有DM2的成年人与40岁的成年人之间的分数各向异性(FA)、径向扩散系数(RD)和轴向扩散系数 和性别匹配的对照组。在目标2中，我将确定脑白质完整性的测量之间的关系 FA和RD)具有认知和运动终点。在目标3中，我将进行试点概念验证研究，以 描述DM2患者脑脊液和血浆中tau蛋白的特征，并将这些发现与 测量大脑结构和认知终点。拟议的综合研究、指导和 授课培训，结合维克森林大学健康学院出色的研究环境 理科，将培养我的长期职业目标，成为一名独立的调查员，具有知识和 领导中枢神经系统表现的神经生物学研究以及最终测试新奇事物的临床试验的技能 改善DM2患者预后和生活质量的靶向治疗机制。

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.