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.

通过自动神经影像学在高清大脑内的病理传播亨廷顿氏病（HD）是一种由CAG扩展引起的进行性致命神经退行性疾病在亨廷顿蛋白中膨胀的聚谷氨酰胺伸展的亨廷顿基因中重复。 HD中的神经变性很大程度上是由异常HTT蛋白的毒性作用引起的，并且有越来越多的证据表明突变体HTT可以像王子一样传播，并且像其他的异常蛋白神经退行性疾病，从一个神经元到另一种神经元。阐明萎缩的序列和模式 HD大脑具有“基因沉默”或“降低RNA”试验的特殊当前重要性，使用反义积极发育中的寡核苷酸，或SHRNA或相关试剂。这些试验成功的关键将要知道何时何时干预，因为这些试剂不会穿透血脑屏障，并且必须注入中枢神经系统。我们的研究将阐明HD传播的暂时和空间模式神经变性，以阐明HD的发病机理并帮助指导介入试验。在特定目标中 1，我们将对体积的空间和临时模式进行横截面和纵向分析与对照大脑相比，使用纵向T1和DTI相比，HD子区域的变化和形状变化从高清病例和预测HD研究和Track-HD研究中进行扫描。扫描会通过Mricloud进行自动处理，分为大约400个子区域。我们假设萎缩将从纹状体开始，然后依次扩散到相邻的白质，然后再传播到皮质灰色事情。或者，变性可能是多灶性的。在特定目标2中，我们将确定 AIM 1的大脑萎缩。在特定的目标3中，我们将使用道追踪方法研究高清大脑中的病理学。我们假设HD脑中萎缩的传播遵循轴突连通性。在线，病理可能以多焦点方式开始并传播。总之，这些研究将描述HD大脑中病理的纵向传播，其临床后果。该信息将阐明HD的发病机理，对于设计至关重要计划介入试验的时间和本地化。

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。