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.

抽象的 最近的转基因小鼠研究突出了可能与之相关的糖糖功能受损 阿尔茨海默氏病（AD）的病理生理学。我们从这些研究中学到的，降低了CSF的清除率， 在淀粉样斑块的开发中需要考虑携带Aβ和其他废物的产品 并且可能是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反式特征 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了受损的 在AD患者中向CSF清除Aβ。但是，腰椎穿刺研究并不能区分 Aβ跨机制的运输受损，来自CSF的大容量流动中的损伤，该机制运输了Aβ。 我们开发了第一种非侵入性技术来量化人类CSF清除率。该技术使用宠物 动态成像具有高脑外渗，快速清除率和有限的低分子量Tau示踪剂 残留的大脑吸收。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以及tau和淀粉样蛋白宠物示踪剂中高度可重现。 CSF清除率达到了89％的AD诊断精度。最重要的是，我们的结果表明 在通风和扣带回时测量的Tau示踪剂清除率（Aβ沉积物的主要目标） 与PIB-PET测量的脑Aβ沉积物的大小密切相关。这种强大的倒数 清除率与Aβ沉积之间的关系在正常（NL）的两个区域和 体素水平。这些观察结果证明了我们对CSF之间关系的前瞻性纵向研究 清除，Aβ病变的进展，脑萎缩和认知能力下降。该研究将注册两个年龄和性别 匹配的NL组：淀粉样蛋白阳性和淀粉样蛋白阴性对照。我们的初步数据也揭示了 上鼻涡轮是人类的CSF出口途径。这个新颖的观察需要 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。总而 使用一种新颖的PET方法来量化CSF从人脑的排水，我们有第一个机会 为了测试csf清除率障碍临床前阿尔茨海默氏病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