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.

通过自动神经成像追踪hd脑内病理扩散