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.

阿尔茨海默病（AD）是痴呆症的最常见原因，目前， 仅在美国就有超过五百万人患有AD。阿尔茨海默病的病因 是未知的，治疗方法才刚刚开始开发。神经质的积累 斑块（Aβ）和神经纤维缠结（NFT）及神经元变性是主要的病理改变 AD的组织病理学特征。然而，在痴呆症的早期阶段诊断AD 不能简单地通过淀粉样蛋白成像来确定，因为许多健康的老年人大脑 Aβ沉积不会导致痴呆。因此，可以提供更多信息的附加标记物 需要准确的神经变性信息，特别是在早期阶段。大脑 淋巴系统，又称胶质淋巴系统，是近年来发现的一种脑脊液 (CSF)循环系统，其利用血管周围通道来消除可溶性蛋白质， 代谢物。胶质淋巴系统的功能障碍促进了Aβ沉积， 脑膜并引起灌注减少和认知障碍。一个关键的障碍， 理解CSF周转包括胶质淋巴系统是缺乏非侵入性方法 其可以应用于询问体内胶质淋巴系统的多个方面。 我们最近开发了几种非侵入性MRI方法，可以评估CSF 分泌和再吸收。这些包括分子成像方法， 具有共振可变延迟多脉冲的动态葡萄糖增强（DGE）成像 （onVibration）MRI。以及一套基于自旋标记的MRI方法，称为磁化 转移间接自旋标记（MISL）和零恢复相位交替标记（PALAN）。 这些后一种方法通过利用它们的显著性来选择性地标记室旁组织。 不同的蛋白质浓度和水的T1、T2、C和扩散特性。PALAN 方法也可在无造影剂的情况下评价脑内ISF血流。我们的长期目标是 开发几种临床上可转换的MRI方案，可以非侵入性地检测CSF， 脑间质液水交换，并将其作为潜在的MRI生物标志物， 早期AD