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.

项目摘要该K23应用的总体目标是评估大脑结构与功能之间的关系关于2型肌发育症（DM2）的认知和运动性能，从而有助于候选人准备独立领导未来的研究，以阐明DM2的神经生物学。虽然肌肉无力是DM2的关键症状，几乎70％的患者报告认知受损是最残疾的症状，并深深影响其生活质量。 DM2，一种多方面的遗传疾病，由CCTG重复膨胀在细胞核酸结合蛋白（CNBP）基因中的结果，其中 RNA功能获取是主要的疾病机制。虽然DM2与Myotonic有几个区别营养不良1型（DM1），它们具有一些遗传和临床相似性，例如实质性认知症状和肌肉无力。在过去十年中，DM1中脑成像的研究有所增加，但相对关于DM2如何影响大脑结构和功能作为DM2中的大脑成像研究的功能知之甚少极有限。这些研究的结果由于样本量较小而产生了矛盾的结果，缺乏定量分析和认知测量之间的差异。但是，大多数发现表明，与对照组相比，脑白质（WM）主要在DM2中受到影响，WM体积降低和从扩散张量成像（DTI）得出的异常WM完整性。新兴的证据已经确定了tau的错误 DM2中的剪接和缠结病理学，这引起了人们对阐明Tau在DM2相关的作用的兴趣认知障碍。最近对WM完整性之间关系的研究强调了这种可能性阿尔茨海默氏病（AD）和阿尔茨海默氏病中的皮质Tau沉积和脑脊液（CSF）TAU 疾病相关痴呆症（ADRD）。然而，迄今为止，还没有研究TAU在DM2中的作用。在总和，目的地明确的认知症状表明中枢神经系统参与，没有研究对 CNS病理学的大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中。在AIM 1中，我将评估白质完整性的脑形态计和DTI测量，包括分数各向异性（FA），径向扩散率（RD）和40名DM2与40岁成年人之间的轴向扩散率和性匹配的控制。在AIM 2中，我将确定白质完整性度量的关系（脑 FA和RD）具有认知和运动端点。在AIM 3中，我将进行一项试点概念证明研究表征DM2患者CSF和血浆中的TAU谱图，并将这些发现与大脑结构和认知终点的度量。拟议的综合研究，指导和教学培训，加上Wake Forest University Health的杰出研究环境科学，将促进我的长期职业目标，以成为知识和知识的独立调查员领导有关中枢神经系统表现神经生物学以及最终测试新颖的临床试验的技能针对DM2患者的预后和生活质量的疗法靶向机制。