PET Measures of CSF Clearance in Preclinical Alzheimer's Disease

临床前阿尔茨海默氏病脑脊液清除率的 PET 测量

• 批准号: 10085704
• 负责人: MONY J. de LEON
• 金额: $ 284.48万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10085704
• 关键词: PET; Measures; CSF; Clearance; Preclinical

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.

摘要 最近的转基因小鼠研究强调了受损的胶质淋巴功能可能参与了 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和其他废物，需要在淀粉样斑块的发展中考虑 可能还有阿尔茨海默氏症的病理生理学这些观察结果补充了良好的特征性反式- 阿尔茨海默氏症中的膜Aβ清除障碍腰椎穿刺研究已经证实 AD患者CSF中Aβ的清除率。然而，腰椎穿刺研究并不能区分 由于运输Aβ的CSF整体流量受损，导致A β跨膜转运受损。 我们开发了第一种非侵入性技术来量化人类CSF清除率。该技术使用PET， 动态成像低分子量tau示踪剂，其具有高脑转移率、快速清除和有限的 残留脑摄取我们的初步数据表明，在控制血液示踪剂水平后，PET CSF清除率的估计值在受试者内以及在tau和淀粉样蛋白PET示踪剂之间是高度可重复的。 CSF清除率诊断AD的准确率达到89%。最重要的是，我们的研究结果表明， 在脑室和扣带回（Aβ沉积的主要靶点）测量的tau示踪剂清除率降低 与PiB-PET测量的脑Aβ沉积量密切相关。这个强逆 在正常老年人（NL）中也发现了清除率与Aβ沉积的关系， 体素水平。这些观察结果证明了我们对CSF与脑梗死之间关系的前瞻性纵向研究是正确的。 清除、Aβ病变进展、脑萎缩和认知能力下降。该研究将招募两名年龄和性别 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 上级鼻甲是人类脑脊液的排出通道。这种新的观察需要 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。总的来说， 使用一种新的PET方法来量化从人脑中排出的CSF，我们有机会 检验CSF清除率受损促进临床前阿尔茨海默病中Aβ传播的假设。

项目成果

Association between liver fibrosis and incident dementia in the UK Biobank study.

• DOI: 10.1111/ene.15437
• 发表时间: 2022-09
• 期刊: European journal of neurology
• 影响因子: 5.1

Tau PET following acute TBI: Off-target binding to blood products, tauopathy, or both?

急性 TBI 后的 Tau PET：与血液制品的脱靶结合、tau 蛋白病变，或两者兼而有之？

• DOI: 10.3389/fnimg.2022.958558
• 发表时间: 2022
• 期刊: Frontiers in neuroimaging
• 作者: Butler,Tracy;Chiang,GloriaC;Niogi,SumitNarayan;Wang,XiuyuanHugh;Skudin,Carly;Tanzi,Emily;Wickramasuriya,Nimmi;Spiegel,Jonathan;Maloney,Thomas;Pahlajani,Silky;Zhou,Liangdong;Morim,Simon;Rusinek,Henry;Normandin,Marc;Dyke,Jona
• 通讯作者: Dyke,Jona