CSF Clearance with 11C-Butanol PET Predicts Amyloid Deposition

摘要 最近的转基因小鼠研究已经强调受损的胶质淋巴功能有助于 阿尔茨海默病（AD）的病理生理学。我们从这些研究中了解到，CSF清除率降低， 携带Aβ和废物等蛋白质，需要在淀粉样蛋白的发展中加以考虑 斑块和AD的病理生理学。这些新兴的观察补充了良好的特点，反式- AD中内皮Aβ清除障碍。腰椎穿刺研究已经证实 AD患者脑脊液中标记Aβ的浓度。然而，腰椎穿刺研究不能区分受损的跨- Aβ的膜转运与CSF流动损伤有关。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，以量化CSF清除率。该技术使用PET动态地 具有高脑转移率、快速清除和有限残留脑低分子量示踪剂成像 摄取。在控制血液示踪剂水平后，我们的初步数据表明，脑室（v）CSF 清除达到89%的准确性诊断AD。vCSF清除率的PET估计值非常高 在受试者内跨PET示踪剂对相关。我们的初步研究还显示， 未记录的上级鼻甲骨脑脊液流出通道。最重要的是，在正常老年人（NL）CSF中， 在脑室和扣带回（Aβ沉积的靶点）测量的清除率与 用11 C-PiB PET测量脑Aβ沉积量。这些观察结果证明了我们提出的 CSF清除率与Aβ病变进展、脑萎缩和 认知能力下降本研究将入组90例年龄和性别匹配的PiB阳性和PiB阴性NL受试者。 为了避免示踪剂结合的混杂效应，我们建议使用11 C-丁醇，一种可自由扩散的示踪剂， 20年前合成，半衰期足以进行CSF测量。总之，该项目提供了第一个 在一项假设检验中，有机会绘制脑和颅外部位的CSF清除率， CSF清除率预测Aβ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.