CSF Clearance with 11C-Butanol PET Predicts Amyloid Deposition

摘要 最近的转基因小鼠研究强调淋巴功能受损是导致 阿尔茨海默病的病理生理学。我们从这些研究中了解到，脑脊液清除量的减少， 它携带像Aβ这样的蛋白质和废物，在淀粉样蛋白的发展中需要考虑 斑块与阿尔茨海默病的病理生理。这些紧急观察补充了具有良好特征的反式- 阿尔茨海默病患者内皮Aβ清除功能受损。腰椎穿刺术证实清除功能受损 阿尔茨海默病患者脑脊液标记A-β的临床意义然而，腰椎穿刺术的研究并不区分转运蛋白受损。 脑脊液流量受损时Aβ的膜转运。我们开发了第一个非侵入性技术， 扩展了传统的动力学模型以定量测定脑脊液清除量。这项技术使用PET来动态地 想象一种低分子示踪剂，具有高脑透过率、快速清除和有限的脑残留 领悟。在控制了血液示踪剂水平后，我们的初步数据表明，脑室(V)脑脊液 Clearance对AD的诊断准确率达到89%。PET对vcsf清除的估计很高。 在受试者中通过成对的PET示踪剂进行关联。我们的初步研究还揭示了之前 未经证实的鼻甲上段脑脊液出口通路。最重要的是，在正常老年人(NL)脑脊液中 在脑室和扣带回(Aβ沉积的目标)测量的清除量呈负相关 用~(11)C-PIBPET测量脑A-β沉积的大小。这些观察结果证明我们的建议是合理的 脑脊液清除量与β病变进展、脑萎缩及预后关系的纵向研究 认知能力下降。这项研究将招募90名年龄和性别匹配的PIB阳性和PIB阴性的NL受试者。 为了避免示踪剂结合的混杂效应，我们建议使用可自由扩散的示踪剂11C-丁醇 20年前合成的，半衰期足以测量脑脊液。总而言之，这个项目提供了第一个 有机会绘制脑和颅外部位的脑脊液清除图，以检验这一假说 脑脊液清除可预测β沉积。

ABSTRACT Recent transgenic mouse studies have highlighted impaired glymphatic function as contributing to the pathophysiology of Alzheimer's disease (AD). We learn from these studies that a reduced clearance of CSF, which carries proteins like Aβ and waste products, needs to be considered in the development of amyloid plaques and pathophysiology of AD. These emergent observations complement the well characterized trans- endothelial Aβ clearance impairments in AD. Lumbar puncture studies have confirmed an impaired clearance of labelled Aβ to the CSF in AD patients. However, lumbar puncture studies do not distinguish impaired trans- membrane transport of Aβ from impairments in CSF flow. We developed the first non-invasive technology and extended the conventional kinetic model to quantify CSF clearance. The technique uses PET to dynamically image a low molecular weight tracer with high brain penetrance, rapid clearance, and limited residual brain uptake. After controlling for blood tracer levels, our preliminary data demonstrate that ventricular (v) CSF clearance achieves 89% accuracy for the diagnosis of AD. PET estimates of vCSF clearance are highly correlated within subject across pairs of PET tracers. Our preliminary studies also revealed a previously undocumented superior nasal turbinate CSF egress pathway. Most importantly, in normal elderly (NL) CSF clearance measured at the ventricle and cingulate gyrus (a target for Aβ deposits) was inversely associated with the magnitude of brain Aβ deposits as measured by 11C-PiB PET. These observations justify our proposed longitudinal study of the relationship between CSF clearance and Aβ lesion progression, brain atrophy and cognitive decline. The study will enroll 90 age and gender matched PiB-positive and PiB-negative NL subjects. To avoid the confounding effect of tracer binding, we propose to use 11C-Butanol, a freely diffusible tracer we synthesized 20 years ago, with a half-life adequate for CSF measurement. In sum, this project offers the first opportunity to map CSF clearance from brain and extra-cranial sites in a test of the hypothesis that impaired CSF clearance predicts Aβ deposition.