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.

项目总结/摘要 脑脊液引流病理学是一个潜在的阿尔茨海默病（AD）治疗新靶点 在AD中受损并在AD模型中得到证实。没有非侵入性的技术来测量大脑 人类的CSF清除率（BCC）。低分子量PET示踪剂，例如18F-MK 6240、18F-THK 5351和18F-THK 5352。 11 C-PiB与其他ISF溶质一样，迅速进入并清除大脑。它们可以自由地通过血脑屏障，分布到 脑和ISF空间，并通过胶质淋巴系统进入脑室CSF。我们已经开发 一种使用放射性示踪剂从脑的清除作为胶质淋巴清除的生物标志物的方法。我们最近的论文 初步的动态PET研究表明，放射性示踪剂在脑室CSF中的分布从35到60 vCSF-AUC（vCSF-min）是估计BCC的有价值的指标。我们的初步数据表明， 通过控制血液示踪剂水平，vCSF-AUC在tau蛋白和淀粉样蛋白受试者中具有高度重现性 PET示踪剂，并实现90%的准确性，正常和受损受试者之间的组分离。BCC 与脑淀粉样蛋白沉积、认知能力和皮质厚度呈负相关， 控制混淆。这些观察结果证明了我们提出的为期2年的纵向研究，以评估 vCSF-AUC作为Aβ沉积的总体预测因子。其次，我们会在年初研究清拆赤字， AD的分期以及与神经退行性变特征（萎缩和认知功能）的相关性。本研究 一个新的尝试，以提高我们的理解提出的机制为AD。我们预计该项目将 促进对AD的危险因素、流行病学、预防和治疗的研究。