Cerebrospinal fluid exchange in Alzheimer's disease characterized by advanced MRI techniques

以先进 MRI 技术为特征的阿尔茨海默病脑脊液交换

• 批准号: 10565781
• 负责人: JIadi Xu
• 金额: $ 71.09万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-15 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10565781
• 关键词: Acetazolamide; Age; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer’s disease biomarker; Amyloid beta-Protein; Animal Disease Models; Animals; Appearance; Biological Markers; Brain; Cerebrospinal Fluid; Circulation; Clinical; Contrast Media; Data; Dementia; Dependence; Deposition; Development; Diagnostic; Diffusion; Disease; Elderly; Etiology; Evaluation; Fluids and Secretions; Foundations; Gadolinium; Glucose; Goals; Human; Huntington Disease; Image; Image Enhancement; Impaired cognition; In Situ; Infusion procedures; Injections; Intercellular Fluid; Intrathecal Injections; Intravenous; Knockout Mice; Label; Liquid substance; Magnetic Resonance Imaging; Measurement; Measures; Meninges; Methods; Monitor; Motion; Multiple Sclerosis; Mus; Names; Nerve Degeneration; Neurofibrillary Tangles; Neurotic Disorders; Non-Invasive Detection; Parkinson Disease; Pathology; Patients; Perfusion; Persons; Phase; Physiologic pulse; Process; Property; Proteins; Recovery; Scheme; Senile Plaques; Signal Transduction; Spin Labels; System; Techniques; Therapeutic; Time; Tissues; Tracer; Translating; Vasopressins; Water; Wild Type Mouse; abeta deposition; absorption; amyloid imaging; aquaporin 4; brain parenchyma; cerebral atrophy; clinical translation; early detection biomarkers; fluid flow; glymphatic dysfunction; glymphatic system; imaging modality; in vivo; longitudinal design; magnetic resonance imaging biomarker; mild cognitive impairment; molecular imaging; mouse model; neurofibrillary tangle formation; neuropathology; perivascular channels; protein aggregation; rapid technique; wasting

Alzheimer's disease (AD) is the most common cause of dementia and, currently, there are more than five million people with AD in the US alone. The etiology of Alzheimer's disease is unknown, and therapies are just starting to be developed. The accumulation of neurotic plaques (Aβ) and neurofibrillary tangles (NFT), and degeneration of neurons are the major histopathological hallmarks of AD. However, a diagnosis of AD in the early stages of dementia cannot be determined simply by amyloid imaging, because many healthy older adults with brain Aβ deposits never develop dementia. Therefore, additional markers that can provide more accurate information of neurodegeneration, particular at the early stage, are needed. The brain lymphatic system, named the glymphatic system, is a recently discovered cerebrospinal fluid (CSF) circulation system that utilizes the perivascular channels to eliminate soluble proteins and metabolite. The dysfunction of the glymphatic system promotes Aβ deposition in the meninges and introduces perfusion reduction and cognitive impairment. A critical barrier for understanding CSF turnover including the glymphatic system is a lack of noninvasive methods that can be applied to interrogate multiple aspects of the glymphatic system in vivo. We recently developed several non-invasive MRI approaches that can assess CSF secretion and reabsorption in situ with MRI. These include a molecular imaging method, dynamic glucose-enhanced (DGE) imaging with on-resonance Variable Delay Multiple Pulse (onVDMP) MRI. as well as a set of spin- labeling based MRI methods, named magnetization transfer indirect spin labeling (MISL) and phase alternate labeling with null recovery (PALAN). These latter methods selectively label the paraventricular tissues by exploiting their significantly different protein concentration and water T1, T2, cand diffusion properties. The PALAN method can also assess the ISF flow in brain without contrast agents. Our long- term goal is to develop several clinically translatable MRI schemes that can non-invasively detect CSF and interstitial fluid water exchange in brain and apply them as potential MRI biomarkers for the early-stage AD.

阿尔茨海默氏病（AD）是痴呆症的最常见原因，目前 仅在美国，就有超过500万人的广告。阿尔茨海默氏病的病因 是未知的，刚开始开发疗法。神经质的积累 斑块（Aβ）和神经原纤维缠结（NFT）以及神经元的变性是主要的 AD的组织病理学标志。但是，在痴呆症的早期诊断AD的诊断 不能简单地通过淀粉样蛋白成像确定，因为许多健康的老年人 Aβ沉积永远不会发展痴呆。因此，可以提供更多的其他标记 需要精确的神经变性信息，特别是在早期阶段。大脑 淋巴系统，称为糖基体系统，是最近发现的脑脊液 （CSF）利用血管周通道消除固体蛋白质和的循环系统 代谢物。糖基系统的功能障碍促进了Aβ的沉积 脑膜和引入灌注减少和认知障碍。一个关键的障碍 理解包括糖浆系统在内的CSF营业额缺乏无创方法 这可以应用于体内糖基体系统的多个方面。 我们最近开发了几种可以评估CSF的非侵入性MRI方法 与MRI的原位分泌和重新吸附。这些包括一种分子成像法， 具有反呼声变量多重脉冲的动态葡萄糖增强（DGE）成像 （ONVDMP）MRI。以及一组基于自旋标记的MRI方法，命名为磁化 带有无效恢复（Palan）的间接自旋标记（MISL）和相位替代标记。 这些以后的方法通过显着利用它们 不同的蛋白质浓度和水T1，T2，CAND差异。佩兰 方法还可以评估大脑中的ISF流量而没有对比剂。我们的长期目标是 开发几种可临床翻译的MRI方案，可以非侵入性检测CSF和 脑间液体水交换在大脑中，并将其作为潜在的MRI生物标志物 早期广告。