Brain Structure and Clinical Endpoints in Myotonic Dystrophy Type 2

2 型强直性肌营养不良的大脑结构和临床终点

基本信息

批准号：
10525819
负责人：
Araya Puwanant
金额：
$ 17.86万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10525819
关键词：
Address Adult Affect Age Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Anisotropy Antisense Oligonucleotides Area Attention Biological Markers Brain Brain Pathology Brain imaging Central Nervous System Diseases Cerebrospinal Fluid Cerebrum Clinical Clinical Trials Cognition Cognitive Cognitive deficits Conflict (Psychology)Cross-Sectional Studies Data Deposition Development Diffuse Diffusion Magnetic Resonance Imaging Disease Disease Progression Environment Fostering Foundations Functional disorder Gait speed Gene Proteins Genetic Genetic Diseases Goals Hand Strength Health Sciences Impaired cognition Knowledge Lead Liquid substance Literature Longitudinal Studies Magnetic Resonance Imaging Measures Memory Mentors Mentorship Methods Motor Muscle Muscle Weakness Myotonic dystrophy type 1 Myotonic dystrophy type 2 Neuraxis Neurobehavioral Manifestations Neurobiology Neurofibrillary Tangles Pathology Patients Performance Plasma Preparation Prospective Studies Protein Isoforms Proxy Quality of life RNA RNA Splicing Radial Reporting Research Research Personnel Role Sample Size Structure Sum Symptoms Testing Training Universities Work career clinically relevant disabling symptom drug development executive function forest gain of function gray matter imaging biomarker imaging study improved outcome interest morphometry motor disorder new therapeutic target normal aging nucleic acid binding protein processing speed sex skills success tau Proteins tau-1 treatment response trial design white matter

项目摘要

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.

项目概要该 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 2 型强直性肌营养不良 (DM2) 的认知和运动表现，从而有助于候选人准备独立领导未来的研究，阐明 DM2 的神经生物学。肌肉无力是 DM2 的主要症状，近 70% 的患者报告认知受损是其中之一 DM2 是一种多方面的遗传性疾病，是最严重的残疾症状，并严重影响他们的生活质量。来自细胞核酸结合蛋白 (CNBP) 基因中 CCTG 重复扩增的结果，其中尽管 DM2 与肌强直有一些区别，但 RNA 功能获得是主要的疾病机制。 1 型营养不良 (DM1)，它们具有一些遗传和临床相似性，例如明显的认知症状虽然在过去十年中，对 DM1 的脑成像研究有所增加，但相对而言。人们对 DM2 如何影响大脑结构和功能知之甚少，因为 DM2 的脑成像研究还处于起步阶段。由于样本量小、缺乏研究，这些研究的结果非常有限。然而，大多数定量研究结果表明，与对照组相比，脑白质 (WM) 主要受到 DM2 的影响，WM 体积减少，来自弥散张量成像 (DTI) 的异常 WM 完整性已发现 tau 错误。 DM2 中的剪接和缠结病理学，这引起了人们对阐明 tau 在 DM2 相关中的作用的兴趣最近关于 WM 完整性之间的研究强调了这种可能性的关系。阿尔茨海默病 (AD) 和阿尔茨海默病中的皮质 tau 沉积和脑脊液 (CSF) tau 然而，迄今为止还没有研究评估 tau 在 DM2 中的作用。总而言之，尽管有明显的认知症状表明中枢神经系统受累，但没有研究仔细评估中枢神经系统病理学的脑结构和液体生物标志物关系及其与认知和运动测量的关系在 DM2 中，我将评估脑形态测量和白质完整性的 DTI 测量，包括 40 名 DM2 成人与 40 岁年龄组之间的分数各向异性 (FA)、径向扩散率 (RD) 和轴向扩散率在目标 2 中，我将确定白质完整性（大脑）测量之间的关系。 FA 和 RD）以及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 DM2 患者脑脊液和血浆中的 tau 蛋白谱，并将这些发现与拟议的综合研究、指导和认知终点的测量。教学培训，结合维克森林大学健康中心出色的研究环境科学，将培养我的长期职业目标，成为一名拥有知识和能力的独立研究者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颖的临床试验的技能针对改善 DM2 患者预后和生活质量的机制的疗法。