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 阿尔茨海默病的病理生理学涉及多种结构和功能异常 多个大脑结构和相关回路，包括关键枢纽海马体的神经退行性变 负责记忆和执行功能。虽然在记录标志方面取得了进展 该疾病的病理生理学，导致海马萎缩、记忆丧失的事件顺序， 由于缺乏in- 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 的旋转框架 MRI 松弛映射，如 神经退行性变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： 将要研究的旋转框架松弛参数使我们能够探测慢运动分量 与标准自由进动 MRI 指标不同的谱密度函数。这种慢动作方式是最 与我们在组织中分子和细胞水平上表征多种生物过程相关 其他人已经在其他病症中得到了证明。因此，我们的总体假设是绝热 T1ρ 将 作为海马神经退化的早期标志物，而 RAFFn 将能够检测到 脱髓鞘，这两种标记物都与阿尔茨海默病不同阶段的神经网络功能障碍相关 通过静息态功能 MRI 检测到的疾病。对此进行调查将追求三个具体目标 假设：1）优化参数以获得旋转框架 MRI 指标的高分辨率映射 从海马亚区域和层中，2) 识别脑组织异常的旋转框架 MRI 标记 在阿尔茨海默氏症大鼠模型中与年龄匹配的 wile 型大鼠进行比较，3) 揭示阿尔茨海默氏症 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，如 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退行性变的新型生物标记物的潜力 扩展母基金中提议的技术开发。空间基因组分析将使我们能够识别 MRI 结果的分子基础，从而提供优化所需的宝贵验证 疗法，监测治疗反应并支持后续在人类中的应用。