Technology to Realize the Full Potential of UHF MRI (Supplement)

充分发挥 UHF MRI 潜力的技术（补充）

• 批准号: 10285102
• 负责人: Gregory John Metzger
• 金额: $ 37.72万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10285102
• 关键词: Achievement; Address; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Atrophic; Biological Markers; Biological Process; Brain; Brain Diseases; Brain region; Cell Death; Choline; Demyelinations; Development; Disease; Disease Management; Disease Progression; Event; Exhibits; Frequencies; Functional Magnetic Resonance Imaging; Functional disorder; Future; Genomics; Glioma; Goals; Hippocampal Formation; Hippocampus (Brain); Histology; Human; Image; Intervention; Knowledge; Lead; Lesion; Magnetic Resonance Imaging; Memory; Memory Loss; Methods; Modality; Modeling; Molecular; Monitor; Motion; Mucopolysaccharidosis I; Multiple Abnormalities; Multiple Sclerosis; Mus; Myelin; Nerve Degeneration; Neurologic Deficit; Outcome; Parkinson Disease; Pathologic; Pathology; Patients; Physiologic pulse; Process; Rattus; Relaxation; Resolution; Rest; Rotation; Scheme; Stroke; Structure; Substantia nigra structure; Technology; Time; Tissues; United States National Institutes of Health; Validation; Work; age related; aphakia mice; base; brain abnormalities; brain tissue; cohort; density; dopaminergic neuron; executive function; gene therapy; hippocampal subregions; human subject; imaging biomarker; in vivo; innovation; insight; magnetic resonance imaging biomarker; mouse model; network dysfunction; neural network; neurogenesis; novel; novel marker; parent grant; therapy development; transcriptome; treatment optimization; treatment response; virtual

ABSTRACT The pathophysiology of Alzheimer’s disease involves a plethora of structural and functional abnormalities of multiple brain structures and related circuits, including neurodegeneration of the hippocampus, a critical hub responsible for memory and executive function. While progress has been made in documenting the hallmarks of the disease’s pathophysiology, the sequence of events that lead to hippocampus atrophy, loss of memory, and loss of executive function with disease progression remain insufficiently characterized due to the lack of in- vivo markers sensitive to the process of neurodegeneration. To address this unmet need our goal is to establish rotating frame MRI relaxation mapping based on Frequency Swept (FS) pulses, adiabatic T1ρ and RAFFn, as novel, non-invasive biomarkers of neurodegeneration and demyelination. This goal is supported by the fact that the rotation frame relaxation parameters that will be investigated, allow us to probe slow motional components of the spectral density function unlike standard free-precession MRI metrics. This slow motional regime is most relevant to characterize multiple biological processes at the molecular and cellular levels in tissue as we and others have demonstrated in other pathologies. As such, our overarching hypothesis is that adiabatic T1ρ will serve as an early marker of neural degeneration of the hippocampus, while RAFFn will be able to detect demyelination, and both markers will correlate with neural network dysfunction at different stages of Alzheimer’s disease, as detected by resting state functional MRI. Three specific aims will be pursued to investigate this hypothesis: 1) optimization of parameters for obtaining high-resolution mapping of rotating frame MRI metrics from hippocampal subregions and layers, 2) identify rotating frame MRI markers of brain tissue abnormalities in a rat model of Alzheimer’s disease as compared to age-matched wile-type rats and 3) uncover the Alzheimer’s disease pathophysiological substrates that best correlate with the novel rotating frame MRI biomarkers, as revealed by resting-state fMRI, histology and spatial genomics. Accomplishing these aims will establish the potential of rotating frame MRI markers as novel biomarkers of neurodegeneration in Alzheimer’s disease by extending technical developments proposed in the parent grant. Spatial genomic analysis will allow us to identify the molecular basis of the MRI outcomes, thus providing an invaluable validation needed for optimizing therapies, monitoring treatment response and supporting subsequent applications in humans.

摘要 阿尔茨海默氏病的病理生理学涉及大量的结构和功能异常， 多个大脑结构和相关电路，包括海马体的神经变性，海马体是一个关键的枢纽， 负责记忆和执行功能。虽然在记录这些特征方面取得了进展， 疾病的病理生理学，导致海马萎缩，记忆丧失， 以及随着疾病进展而丧失执行功能，由于缺乏信息， 对神经变性过程敏感的体内标记物。为了解决这一未满足的需求，我们的目标是建立 基于扫频（FS）脉冲、绝热T1ρ和RAFFn的旋转帧MRI弛豫映射， 神经变性和脱髓鞘的新型非侵入性生物标志物。这一目标得到以下事实的支持： 将被研究旋转框架松弛参数，允许我们探测慢运动分量 与标准的自由旋进MRI指标不同，这种缓慢运动的制度是最 与表征组织中分子和细胞水平上的多种生物过程相关， 其他的已经在其他的病理学中表现出来。因此，我们的首要假设是绝热T1ρ将 作为海马神经退化的早期标志，而RAFFn将能够检测到 脱髓鞘，这两个标志物将与阿尔茨海默病不同阶段的神经网络功能障碍相关 疾病，如通过静息状态功能性MRI检测。将追求三个具体目标来调查这一点 假设：1）优化用于获得旋转框架MRI度量的高分辨率映射的参数 从海马亚区和层，2）识别脑组织异常的旋转框架MRI标记物 与年龄匹配的Wile型大鼠相比，在阿尔茨海默病大鼠模型中， 与新型旋转框架MRI生物标志物最相关的疾病病理生理学底物， 通过静息态功能磁共振成像、组织学和空间基因组学揭示。实现这些目标将建立 旋转框架MRI标记物作为阿尔茨海默病神经变性新生物标志物的潜力 扩展母赠款中提出的技术发展。空间基因组分析将使我们能够识别 MRI结果的分子基础，从而提供了优化所需的宝贵验证 治疗，监测治疗反应和支持后续应用于人类。