CSF Clearance in Sporadic Alzheimer's Disease

散发性阿尔茨海默病的脑脊液清除率

• 批准号: 9981182
• 负责人: Yi Li
• 金额: $ 82.77万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9981182
• 关键词: Abeta clearance; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloid beta-Protein; Amyloid deposition; Anatomy; Area; Astrocytes; Atrophic; Binding; Biological Markers; Blood; Brain; Brain Pathology; Brain imaging; Cerebrospinal Fluid; Characteristics; Clinical; Clinical Trials; Cognition; Communication; Core-Binding Factor; Data; Deposition; Development; Diagnosis; Disease Progression; Dose; Drainage procedure; Elderly; Enrollment; Epidemiology; Excision; Failure; Follow-Up Studies; Functional disorder; Human; Image; Impaired cognition; Impairment; Intercellular Fluid; Lesion; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Methods; Molecular Weight; Nerve Degeneration; Neurofibrillary Tangles; Paper; Pathology; Positron-Emission Tomography; Prevention; Publications; Publishing; Reproducibility; Research; Research Design; Research Personnel; Risk Factors; Role; Senile Plaques; Standardization; Techniques; Testing; Thick; Tracer; Ventricular; Work; abeta deposition; cerebral atrophy; cognitive function; cognitive performance; expectation; experience; follow-up; glymphatic system; improved; novel; radiotracer; recruit; research clinical testing; solute; tau Proteins; therapeutic target; water channel

PROJECT SUMMARY / ABSTRACT CSF drainage pathology, a potential new Alzheimer's disease (AD) therapeutic target, has been hypothesized as impaired in AD and demonstrated in AD models. There is no non-invasive technique to measure the brain CSF clearance (BCC) in humans. Low molecular weight PET tracers such as 18F-MK6240, 18F-THK5351 and 11C-PiB, like other ISF solutes, rapidly enter and clear the brain. They can freely pass the BBB, distribute into brain and ISF spaces, and move into the ventricular CSF through the glymphatic system. We have developed a method to use radiotracer clearance from brain as a biomarker for glymphatic clearance. Our recent paper and preliminary dynamic PET studies demonstrate that radiotracer distribution in ventricular CSF from 35 to 60 minutes (vCSF-AUC) is a valuable marker to estimate BCC. Our preliminary data demonstrate that after controlling for blood tracer levels, vCSF-AUC are highly reproducible within subjects across tau and amyloid PET tracers and achieve 90% accuracy for group separation between normal and impaired subjects. BCC correlated inversely with brain amyloid deposition, cognitive performance and cortical thickness even after controlling for confounds. These observations justify our proposed 2-year longitudinal study to evaluate the vCSF-AUC as a global predictor of Aβ deposition. Secondarily, we will examine the clearance deficit in early stages of AD and association with features of neurodegeneration (atrophy and cognitive function). This study is a novel attempt to improve our understanding of a proposed mechanism for AD. We anticipate this project will facilitate research into the development of risk factors, epidemiology, prevention and treatment of AD.

项目摘要 /摘要 CSF引流病理学是一种潜在的新阿尔茨海默氏病（AD）治疗靶标的，已被假设 正如AD中受损的，并且在AD模型中证明。没有无创的技术来测量大脑 人类中的CSF清除（BCC）。低分子量宠物示踪剂，例如18F-MK6240、18F-THK5351和 与其他ISF太阳能一样，11C-PIB迅速进入并清除大脑。他们可以自由地通过BBB，分发 大脑和ISF空间，并通过糖基系统进入心室CSF。我们已经发展了 一种使用大脑的放射性示意剂清除率作为糖浆清除率的生物标志物的方法。我们最近的论文 初步动态宠物研究表明，心室CSF的放射性示意剂分布从35到60 分钟（VCSF-AUC）是估计BCC的宝贵标记。我们的初步数据表明 在控制tau和淀粉样蛋白的受试者中，VCSF-AUC控制血液示踪剂水平高度可重现 宠物示踪剂并达到90％的准确性，用于正常受试者和受损受损之间的群体分离。 BCC 即使在 控制混杂。这些观察结果证明了我们提出的两年纵向研究的合理性，以评估 VCSF-AUC作为Aβ沉积的全局预测指标。次要，我们将检查早期的清除赤字 AD阶段以及与神经变性（萎缩和认知功能）的特征相关联。这项研究是 一种新颖的尝试，试图提高我们对提出的AD机制的理解。我们预计这个项目将会 促进研究风险因素的发展，流行病学，预防和AD的治疗。