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.

抽象的 阿尔茨海默氏病的病理生理涉及多种结构和功能异常 多个大脑结构和相关电路，包括海马的神经变性，关键枢纽 负责记忆和执行功能。虽然在记录标志方面取得了进展 在该疾病的病理生理学中，导致海马萎缩，记忆力下降的事件序列， 疾病进展的执行功能的丧失由于缺乏侵入而无法充分表征 体内标记对神经变性过程敏感。解决这个未满足的需求是我们的目标 旋转框架MRI松弛映射基于频率扫描（FS）脉冲，绝热T1ρ和RAFFN，AS 新颖的神经变性和脱髓鞘的非侵入性生物标志物。这个目标得到了以下事实的支持 将要研究的旋转框架松弛参数，允许我们探测缓慢的运动组件 光谱密度函数的功能与标准的自由计划MRI指标不同。这种缓慢的动作制度最多 与表征在组织中的分子和细胞水平上表征多个生物学过程有关 其他人在其他病理中也证明了这一点。因此，我们的总体假设是绝热T1ρ将 作为海马神经变性的早期标记，而RAFFN将能够检测到 脱髓鞘，两个标记将与阿尔茨海默氏症不同阶段的神经网络功能障碍相关 疾病，如静止状态功能性MRI所检测到的。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指标高分辨率映射的参数 从海马子区域和层中，2）确定脑组织异常的旋转框架MRI标记 与年龄匹配的wile型大鼠相比，阿尔茨海默氏病大鼠模型中 与新型旋转框架MRI生物标志物最有关系的疾病病理生理底物 由静止状态fMRI，组织学和空间基因组学揭示。完成这些目标将确定 旋转框架MRI标记物作为阿尔茨海默氏病神经退行性的新生物标志物的潜力 扩展父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，因此提供了优化所需的宝贵验证 疗法，监测治疗反应并支持后续的人类应用。