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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

基本信息

批准号：
10155594
负责人：
MICHAEL I MILLER
金额：
$ 59.91万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-15 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10155594
关键词：
Age Alzheimer&apos 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 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 clinical outcome measures 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

项目摘要

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.

通过自动神经成像追踪HD脑中病理学病变的扩散亨廷顿病（HD）是一种进行性致死性神经退行性疾病，由CAG扩张引起亨廷顿蛋白基因中编码亨廷顿蛋白中扩展的多聚谷氨酰胺片段的重复序列。 HD中的神经变性在很大程度上是由异常Htt蛋白的毒性作用引起的，越来越多的证据表明，突变的Htt可以传播，像朊病毒，并像异常蛋白质在其他神经退行性疾病，从一个神经元到另一个。阐明萎缩的顺序和模式， HD脑目前具有特殊的重要性，使用反义核酸进行“基因沉默”或“RNA降低”试验，寡核苷酸或shRNA或相关试剂。这些试验成功的关键是知道何时何地进行干预，因为这些试剂不会穿透血脑屏障，必须注入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变性，阐明HD的发病机制，并帮助指导干预试验。具体目标首先，我们将进行横向和纵向分析的空间和时间模式的体积使用纵向T1和DTI，与对照脑相比，HD亚区的变化和形状变化来自PREDICT-HD研究和TRACK-HD研究的HD病例和对照的扫描。扫描将通过MRICloud进行自动化处理，分为约400个子区域。我们假设萎缩将开始于纹状体，并依次扩散到邻近的白色物质，然后扩散到皮质灰质所谓了或者，变性可能是多灶性的。在具体目标2中，我们将确定以下临床相关性：目标一的脑萎缩在具体目标3中，我们将使用追踪方法来研究 HD大脑的病理学我们假设HD脑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扩散。总之，这些研究将描绘HD脑内病理学的纵向扩散，及其临床后果。这些信息将阐明HD的发病机制，并将是设计计划的干预性试验的时间和地点。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mixed longitudinal and cross-sectional analyses of deep gray matter and white matter using diffusion weighted images in premanifest and manifest Huntington's disease.

DOI：
10.1016/j.nicl.2023.103493
发表时间：
2023
期刊：
NEUROIMAGE-CLINICAL
影响因子：
4.2
作者：
Hu, Beini;Younes, Laurent;Bu, Xuan;Liu, Chin-Fu;Ratnanather, J. Tilak;Paulsen, Jane;Georgiou-Karistianis, Nellie;Miller, Michael I.;Ross, Christopher;Faria, Andreia, V
通讯作者：
Faria, Andreia, V

Longitudinal imaging highlights preferential basal ganglia circuit atrophy in Huntington's disease.

纵向成像突出显示亨廷顿病中优先出现的基底神经节环路萎缩。