Tracing Spread of Pathology Within The HD Brain via Automated Neuroimaging

通过自动神经影像追踪 HD 大脑内病理学的传播

• 批准号: 9924675
• 负责人: MICHAEL I MILLER
• 金额: $ 59.99万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-15 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9924675
• 关键词: Age; Alzheimer' s Disease; Amygdaloid structure; Antisense Oligonucleotides; Atrophic; Axon; Blood - brain barrier anatomy; Brain; Brain Diseases; Brain region; CAG repeat; Cell Nucleus; Cells; Cerebral cortex; Clinical; Clinical Trials; Code; Cognition Disorders; Cognitive; Corpus striatum structure; Data; Development; Diagnosis; Disease Progression; Emotional; Emotional disorder; Exposure to; Gender; Gene Silencing; Genes; Genetic; Hippocampus (Brain); Huntington Disease; Huntington gene; Huntington protein; Image; Intervention; Intervention Trial; Methods; Modeling; Motor; Movement; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Outcome; Outcome Measure; Parkinson Disease; Pathogenesis; Pathologic; Pathology; Pattern; Prion Diseases; Proteins; RNA; Reagent; Scanning; Shapes; Stretching; Structure; Testing; Thalamic structure; Time; Toxic effect; automated analysis; base; case control; cerebral atrophy; clinically significant; cognitive change; design; excitotoxicity; gray matter; innovation; longitudinal analysis; magnetic resonance imaging biomarker; mind control; mutant; neuroimaging; polyglutamine; prion-like; regional atrophy; shape analysis; small hairpin RNA; spatiotemporal; success; white matter

TRACING SPREAD OF PATHOLOGY WITHIN THE HD BRAIN VIA AUTOMATED NEUROIMAGING Huntington's disease (HD) is a progressive fatal neurodegenerative disorder caused by an expanding CAG repeat in the Huntingtin gene coding for an expanding polyglutamine stretch in the Huntingtin protein. Neurodegeneration in HD is in large part caused by toxic effects of the abnormal Htt protein, and there is increasing evidence that mutant Htt can spread, like prions, and like abnormal proteins in other neurodegenerative diseases, from one neuron to another. Elucidating the sequence and pattern of atrophy in the HD brain is of special current importance, with “gene silencing” or “RNA-lowering” trials, using antisense oligonucleotides, or shRNA, or related reagents, in active development. The key to success of these trials will be to know where and when to intervene, since these reagents do not penetrate the blood-brain-barrier, and must be injected into the CNS. Our studies will elucidate the temporal and spatial patterns of the spread of HD neurodegeneration, to elucidate the pathogenesis of HD and to help guide interventional trials. In Specific Aim 1, we will conduct cross sectional and longitudinal analyses of the spatial and temporal pattern of volumetric change and shape change in subregions of HD compared to control brains, using longitudinal T1 and DTI scans from HD cases and controls from the PREDICT-HD study and the TRACK-HD study. Scans will undergo automated processing through MRICloud, segmented into about 400 subregions. We hypothesize that atrophy will begin in the striatum and spread sequentially to adjacent white matter and then to cortical gray matter. Alternatively degeneration may be multifocal. In Specific Aim 2 we will determine clinical correlations of the brain atrophy from Aim 1. In Specific Aim 3 we will use tract-tracing methods to study the spread of pathology in the HD brain. We hypothesize that the spread of atrophy in the HD brain follows patterns of axonal connectivity. Alternatively, it is possible that pathology begins and spreads in a multifocal fashion. Taken together these studies will delineate the longitudinal spread of pathology within the HD brain, and its clinical consequences. This information will elucidate the pathogenesis of HD and will be critical for designing the timing and localization of planned interventional trials.

通过自动神经影像追踪 HD 大脑内的病理传播 亨廷顿病 (HD) 是一种进行性致命的神经退行性疾病，由 CAG 扩张引起 亨廷顿蛋白中编码扩展的聚谷氨酰胺片段的亨廷顿基因中的重复序列。 HD 中的神经退行性变在很大程度上是由异常 Htt 蛋白的毒性作用引起的，并且 越来越多的证据表明，突变型 Htt 可以像朊病毒一样传播，也可以像其他细胞中的异常蛋白质一样传播。 神经退行性疾病，从一个神经元转移到另一个神经元。阐明萎缩的顺序和模式 HD大脑目前具有特殊的重要性，通过使用反义的“基因沉默”或“RNA降低”试验 寡核苷酸、shRNA 或相关试剂正在积极开发中。这些试验成功的关键是 知道何时何地进行干预，因为这些试剂不能穿透血脑屏障，并且 必须注射到中枢神经系统。我们的研究将阐明 HD 传播的时间和空间模式 神经退行性变，阐明 HD 的发病机制并帮助指导介入试验。特定目标 1、对体积时空格局进行横断面和纵向分析 使用纵向 T1 和 DTI 与对照大脑相比，HD 子区域的变化和形状变化 来自 HD 病例的扫描以及来自 PREDICT-HD 研究和 TRACK-HD 研究的对照。扫描将 通过 MRICloud 进行自动化处理，分为约 400 个子区域。我们假设 萎缩将从纹状体开始，依次扩散到邻近的白质，然后扩散到皮质灰质 事情。或者，变性可能是多灶性的。在具体目标 2 中，我们将确定以下各项的临床相关性： 目标 1 中的脑萎缩。在具体目标 3 中，我们将使用束追踪方法来研究 HD 大脑中的病理学。我们假设 HD 大脑中萎缩的扩散遵循以下模式： 轴突连接。或者，病理可能以多灶性方式开始和传播。 总而言之，这些研究将描绘 HD 大脑内病理学的纵向传播及其 临床后果。这些信息将阐明 HD 的发病机制，对于设计至关重要 计划的干预试验的时间和地点。