CSF Clearance with 11C-Butanol PET Predicts Amyloid Deposition

11C-丁醇 PET 清除脑脊液可预测淀粉样蛋白沉积

• 批准号: 9757509
• 负责人: HENRY RUSINEK
• 金额: $ 32.21万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9757509
• 关键词: Abeta clearance; Age; Aging; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid deposition; Anatomy; Binding; Biochemical; Biological Markers; Blood; Brain; Brain Injuries; Butanols; Cells; Cephalic; Clinical; Cognition; Complement; Cross-Sectional Studies; Data; Deposition; Development; Diffuse; Elderly; Enrollment; Follow-Up Studies; Functional disorder; Future; Gender; Guidelines; Half-Life; Human; Image; Imaging technology; Impaired cognition; Impairment; Intercellular Fluid; Kinetics; Label; Late Onset Alzheimer Disease; Learning; Lesion; Liquid substance; Longitudinal Studies; Magnetic Resonance Imaging; Maps; Measurement; Measures; Memory; Methods; Modeling; Molecular Weight; Nasal cavity; Nasal turbinate bone structure; Nerve Degeneration; Neuropsychology; Nose; Olfactory Nerve; Pathway interactions; Patients; Penetrance; Perfusion; Physiological; Pittsburgh Compound-B; Positron-Emission Tomography; Proteins; Residual state; Rodent; Rodent Model; Running; Sampling; Senile Plaques; Site; Spinal Puncture; Subarachnoid Space; Sum; Techniques; Technology; Testing; Thick; Time; Tissues; Tracer; Transgenic Mice; Transgenic Organisms; Transmembrane Transport; United States National Institutes of Health; Validation; Ventricular; Waste Products; Work; abeta accumulation; abeta deposition; cerebral atrophy; cingulate gyrus; cohort; diagnostic accuracy; disease diagnosis; follow-up; healthy aging; human tissue; indexing; longitudinal design; pre-clinical; radiotracer; tau Proteins; tool; trait; uptake

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.

抽象的 最近的转基因小鼠研究强调了乙二醇功能受损，这有助于 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， 在淀粉样蛋白的发展中需要考虑携带Aβ和废物等蛋白质的蛋白质 AD的斑块和病理生理学。这些紧急观察结果完成了良好特征的反式观测 AD中的内皮Aβ清除障碍。腰椎穿刺研究已证实了通关的受损 在AD患者中标记为CSF的Aβ的标记。但是，腰椎穿刺研究并不能区分跨性别受损 CSF流中Aβ的膜转运。我们开发了第一个非侵入性技术， 扩展了常规动力学模型以量化CSF清除率。该技术使用宠物动态 图像具有高大脑渗透率，快速间隙和有限的残留大脑的低分子量示踪剂 吸收。在控制血液示踪剂水平后，我们的初步数据表明心室（V）CSF 清除率达到了89％的AD诊断精度。 VCSF间隙的宠物估计值高 跨对宠物示踪剂的受试者在受试者中相关。我们的初步研究也揭示了以前的 无证件的上鼻涡轮机CSF出口途径。最重要的是，在正常的（NL）CSF中 在通风和扣带回合（Aβ沉积的目标）上测量的清除率成现成 通过11C-PIB PET测量的脑Aβ沉积的大小。这些观察结果证明了我们提议的 纵向研究CSF清除与Aβ病变进展，脑萎缩和 认知能力下降。该研究将招募90岁的年龄，并匹配性别匹配的PIB阳性和PIB阴性NL受试者。 为了避免示踪剂结合的混杂作用，我们建议使用11C-丁醇，一种自由扩散的示踪剂。 20年前合成，半衰期足以进行CSF测量。总而言之，这个项目提供了第一个 在测试损害的假设中，从大脑和颅外地点绘制CSF清除的机会 CSF清除预测Aβ沉积。