PET Measures of CSF Clearance in Preclinical Alzheimer's Disease

摘要 最近的转基因小鼠研究表明，淋巴功能受损可能参与了 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Aβ和其他废物，在淀粉样斑块的发展中需要考虑 可能是阿尔茨海默氏症的病理生理学。这些观察结果很好地补充了反式 阿尔茨海默氏症患者的膜Aβ清除障碍。腰椎穿刺术研究证实 阿尔茨海默病患者脑脊液中Aβ的清除然而，腰椎穿刺术的研究并不区分 由于运送Aβ的脑脊液大量流动的损害，Aβ的跨膜运输受损。 我们开发了第一项非侵入性技术来量化人类脑脊液清除情况。该技术使用正电子发射计算机断层扫描技术 动态成像低分子量tau示踪剂，具有高脑透视率、快速清除和有限的 残留的大脑摄取。我们的初步数据显示，在控制了血液示踪水平后，PET 对脑脊液清除量的估计在受试者内以及在tau和淀粉样蛋白PET示踪剂之间具有高度的重复性。 脑脊液清除法诊断AD的准确率达89%。最重要的是，我们的结果表明 在脑室和扣带回测量的tau示踪剂清除量减少(Aβ沉积的主要目标) 与PIB-β测量的脑A蛋白沉积的大小密切相关。这个强烈的逆反 在正常老年人(NL)中也发现了Clearance和Aβ沉积的关系 体素级别。这些观察结果证明了我们对脑脊液与脑脊液之间关系的前瞻性纵向研究的合理性。 清除、Aβ病变进展、脑萎缩和认知能力下降。这项研究将招收两个年龄和性别 匹配的NL老年组：淀粉样蛋白阳性和淀粉样蛋白阴性对照。我们的初步数据还显示 上鼻甲是人类脑脊液的出口途径。这种新奇的观察需要 进一步的解剖学和组织学验证，我们建议在探索性研究中收集这些信息。总而言之， 使用一种新的PET方法来量化从人脑中流出的脑脊液，我们有了第一次机会 检验脑脊液清除受损促进临床前阿尔茨海默病患者Aβ传播的假说。

ABSTRACT Recent transgenic mouse studies have highlighted impaired glymphatic function as potentially involved in the pathophysiology of Alzheimer's disease (AD). We learn from these studies that a reduced clearance of CSF, which carries Aβ and other waste products, needs to be considered in the development of amyloid plaques and possibly the pathophysiology of Alzheimer's. These observations complement well characterized trans- membrane Aβ clearance impairments in Alzheimer's. Lumbar puncture studies have confirmed an impaired clearance of Aβ to the CSF in AD patients. However, lumbar puncture studies do not distinguish between an impaired transport of Aβ across membranes from impairments in the bulk flow of CSF, which transports the Aβ. We developed the first non-invasive technology to quantify human CSF clearance. The technique uses PET to dynamically image a low molecular weight tau tracer with high brain penetrance, rapid clearance, and limited residual brain uptake. Our preliminary data demonstrate that after controlling for blood tracer levels, PET estimates of CSF clearance are highly reproducible within subject and across tau and amyloid PET tracers. CSF clearance achieves 89% accuracy for the diagnosis of AD. Most importantly, our results show that reduced tau tracer clearance measured at the ventricle and the cingulate gyrus (a major target for Aβ deposits) is closely associated with the magnitude of brain Aβ deposits as measured by PiB-PET. This strong inverse relationship between clearance and Aβ deposition is also found in normal elderly (NL) at both region and voxels levels. These observations justify our prospective longitudinal study of the relationship between CSF clearance, Aβ lesion progression, brain atrophy and cognitive decline. The study will enroll two age and gender matched NL elderly groups: amyloid-positive and amyloid-negative controls. Our preliminary data also revealed that the superior nasal turbinates are a CSF egress pathway in humans. This novel observation requires further anatomical and histological validation, which we propose to collect in an exploratory study. In sum, using a novel PET method to quantify the drainage of CSF from the human brain, we have the first opportunity to test the hypothesis that impaired CSF clearance facilitates Aβ propagation in preclinical Alzheimer disease.