CSF Clearance in Sporadic Alzheimer's Disease

项目摘要/摘要 脑脊液引流病理学，一个潜在的阿尔茨海默病(AD)治疗的新靶点，已经被假设 在AD中受损，在AD模型中表现出来。没有非侵入性的技术来测量大脑 人体脑脊液清除(BCC)。低分子量PET示踪剂，如18F-MK6240、18F-THK5351和 11C-PIB和其他ISF溶质一样，能迅速进入和清除大脑。他们可以自由地通过BBB，分发到 大脑和ISF空间，并通过淋巴系统进入脑室脑脊液。我们已经开发出 一种用放射性示踪剂从脑清除作为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脑脊液中的分布从35到60 分钟数(vCSF-AUC)是判断BCC的有价值的指标。我们的初步数据表明，在 控制血液示踪剂水平，vcsf-auc在tau和淀粉样蛋白受试者中具有高度重复性。 PET示踪器，并达到90%的准确率，以区分正常和受损的受试者。密件抄送 与脑淀粉样蛋白沉积、认知能力和皮质厚度呈负相关 控制混乱。这些观察结果证明了我们提议的为期两年的纵向研究的合理性 Vcsf-auc作为Aβ沉积的全球预测因子。第二，我们会及早研究清拆赤字。 阿尔茨海默病的分期及其与神经变性特征(萎缩和认知功能)的关系。这项研究是 这是一种新的尝试，旨在提高我们对AD拟议机制的理解。我们预计这个项目将 促进对阿尔茨海默病的危险因素、流行病学、预防和治疗发展的研究。

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.