Neuropathological correlates of the SMBT-1 PET ligand for imaging astrogliosis in Alzheimer's disease

SMBT-1 PET 配体与阿尔茨海默病星形胶质细胞增生成像的神经病理学相关性

• 批准号: 10410731
• 负责人: Milos D Ikonomovic
• 金额: $ 65.68万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10410731
• 关键词: Affinity; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid; Amyloid beta-Protein; Amyloidosis; Area; Astrocytes; Autopsy; Autoradiography; Binding; Biochemical; Biological Assay; Biological Markers; Blood; Blood - brain barrier anatomy; Blood Vessels; Blood specimen; Brain; Brain region; Clinical; Cognition; Cognitive; Dendritic Spines; Disease; Elderly; Enzyme-Linked Immunosorbent Assay; Enzymes; Evaluation; Extravasation; Freezing; Glial Fibrillary Acidic Protein; Goals; Harvest; Image; Imaging ligands; Immunohistochemistry; Impaired cognition; Impairment; In Vitro; Inflammation; Inflammatory; Knowledge; Ligands; Liquid substance; Magnetic Resonance Imaging; Measures; Monoamine Oxidase B; Neurodegenerative Disorders; Participant; Pathogenesis; Pathologic; Pathology; Pattern; Phenotype; Positron-Emission Tomography; Production; Proteins; Proteomics; Resources; Role; Senile Plaques; Series; Serum Proteins; Severities; Signal Transduction; Synapses; Testing; Validation; Variant; Western Blotting; aquaporin 4; astrogliosis; beta amyloid pathology; brain magnetic resonance imaging; brain tissue; cingulate cortex; cytokine; density; imaging biomarker; immunoreactivity; interest; neural circuit; neuroimaging; neuropathology; novel; radioligand; radiotracer; tau Proteins; validation studies; β-amyloid burden

Project 4 Summary/Abstract: The main goal of Project-4 is to provide postmortem neuropathological evaluation of the recently developed SMBT-1 ligand which, due to high affinity for monoamine oxidase B (MAO- B), is a novel positron emission tomography (PET) radiotracer for imaging astrogliosis in Alzheimer’s disease (AD). We propose a series of postmortem studies to determine regional patterns of SMBT-1 binding in relation to MAO-B, glial fibrillary acidic protein (GFAP), and other markers of reactive astrocytes, as well as amyloid-β (Aβ) and tau pathology and synaptic loss in cases with different levels of AD neuropathologic changes. We will accomplish this using autopsy brains banked during previous PPG2&3 cycles, and brains from new PPG4 participants who will be imaged with 18F-SMBT-1 as well as amyloid and tau PET ligands 11C-PiB and 18F-MK- 6240, respectively. In Aim 1, we will test the hypothesis that on postmortem brain sections, 3H-SMBT-1 autoradiography and a novel fluorescent derivative of SMBT-1 (cyano-SMBT-1) correspond strongly to MAO-B/GFAP reactive astrocytes and are associated more closely with Aβ pathology than tau pathology. Complementary analyses of frozen brain homogenates from the same regions/cases will characterize 3H-SMBT-1 binding in relation to MAO- B and GFAP protein levels, Aβ and tau concentrations, and binding levels of 3H-PiB and 3H-MK-6240. In Aim 2, we will determine associations of astrogliosis markers, and Aβ and tau pathologies, with regional synaptic density (a strong correlate of cognition) on postmortem brain sections. Biochemical assays will determine associations of 3H-SMBT-1 binding, astrogliosis-related proteins, 3H-PiB and 3H-MK-6240 binding levels, and Aβ and tau concentrations with regional levels of synaptic proteins in the same brain homogenates. In Aim 3, we propose the first imaging-to-autopsy validation study of 18F-SMBT-1 PET as an imaging biomarker of astrogliosis, and its relation to Aβ and tau pathology, in autopsy brains from the PPG4 participants imaged with 18F-SMBT-1, 11C-PiB, and 18F-MK-6240 PET in Projects 1 and 2. Matching of regions-of-interest on PET scans and postmortem brain slabs will be optimized using ex-vivo 7T MR imaging of autopsy brains. We will also determine how postmortem measures of MAO-B/GFAP and aquaporin-4 correlate with region-matched antemortem analyses of brain fluid dynamics and blood brain barrier using 7T MRI in Project-3. Postmortem analyses of astrogliosis and cytokines in brain tissues will be correlated with biomarkers of inflammation in blood samples collected antemortem from the same subjects. These studies will involve close interactions of Project-4 with other Projects in the PPG, and will contribute new knowledge regarding 18F-SMBT-1 PET as a potentially valuable addition to the neuroimaging panel for AD.

项目4摘要/摘要： Project-4的主要目的是提供死后神经病理学 对最近开发的SMBT-1配体的评估，由于对单胺氧化物B的亲和力高（MAO-） b）是一种新型的正电子发射断层扫描（PET），用于成像阿尔茨海默氏病的星形胶质病 （广告）。我们提出了一系列验尸研究，以确定关系中SMBT-1结合的区域模式 到MAO-B，神经胶质原纤维酸性蛋白（GFAP）和其他反应性星形胶质细胞的标志物以及淀粉样蛋白β （Aβ）和tau病理和突触丧失在具有不同水平的AD神经病理学变化的病例中。我们将 在以前的PPG2和3周期中使用的尸检大脑和新PPG4的大脑来完成此操作 将使用18F-SMBT-1以及淀粉样蛋白和Tau Pet配体11C-PIB和18F-MK-进行成像的参与者 分别为6240。 在AIM 1中，我们将检验以下假设：在尸体后脑部，3H-SMBT-1放射自显影和A SMBT-1（Cyano-SMBT-1）的新型荧光衍生物与MAO-B/GFAP反应性相对应 与TAU病理相比，星形胶质细胞与Aβ病理更紧密相关。补充分析 来自相同区域/病例的冷冻脑匀浆将表征与MAO-相关的3H-SMBT-1结合 B和GFAP蛋白水平，Aβ和TAU浓度以及3H-PIB和3H-MK-6240的结合水平。 在AIM 2中，我们将确定星形胶质症标记的关联以及Aβ和TAU病理学与区域 尸体后脑切片的突触密度（认知的强相关）。生化测定将 确定3H-SMBT-1结合，星形胶质症相关蛋白，3H-PIB和3H-MK-6240结合的关联 水平和Aβ和TAU浓度在同一脑匀浆中具有区域水平的突触蛋白水平。 在AIM 3中，我们提出了第一个对18F-SMBT-1 PET的成像验证研究作为成像 Astogliosis的生物标志物及其与Aβ和TAU病理学的关系，来自PPG4参与者的尸检大脑 在项目1和2中使用18F-SMBT-1，11C-PIB和18F-MK-6240 PET成像。 在PET扫描和验尸后，将使用尸检大脑的Ex-Vivo 7T MR成像进行优化。我们 还将确定MAO-B/GFAP和Aquaporin-4的死后测量与区域匹配 Project-3中使用7T MRI对脑液流体动力学和血脑屏障进行了蚂蚁分析。验尸 脑组织中星形胶质病和细胞因子的分析将与血液中炎症的生物标志物相关 样品从同一受试者中收集了仙信。 这些研究将涉及Project-4与PPG中其他项目的密切相互作用，并将贡献 关于18F-SMBT-1 PET的新知识是对AD神经影像学面板的潜在有价值的补充。