PET imaging of microtubules in cognitively normal and impaired older adults

认知正常和受损老年人的微管 PET 成像

基本信息

批准号：
10915761
负责人：
SUZANNE CRAFT
金额：
$ 92.64万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-30 至 2024-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10915761
关键词：
Address Adult Age Alzheimer disease detection Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease diagnosis Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer’s disease biomarker Amyloid Amyloid beta-Protein Amyloidosis Animal Model Autopsy Autoradiography Axonal Transport Biological Assay Biological Markers Blinded Blood specimen Brain Brain imaging Cell Survival Cell physiology Cerebrospinal Fluid Characteristics Clinical Clinical Trials Cognitive Data Data Sources Dementia Development Diagnosis Disease Disease Progression Drug Kinetics Early Diagnosis Elderly Enrollment Event Female Functional disorder Health Human Image Impaired cognition Impairment In Vitro Individual Lesion Ligands Link MAPT gene Malignant neoplasm of brain Measures Metabolic Microtubule-Associated Proteins Microtubules Modeling Modification Molecular Mus Nerve Degeneration Neurofibrillary Tangles Neurons PET positivity Participant Pathogenesis Pathologic Pathology Persons Positron-Emission Tomography Process Radiometry Reporting Research Rodent Role Safety Scanning Senile Plaques Signal Transduction Staging Stratification Symptoms Synapses Tauopathies Testing Therapeutic Therapeutic Agents Time Tubulin X-Ray Computed Tomography axonopathy brain tissue clinical imaging cognitive testing design early detection biomarkers first-in-human forest human study human subject imaging agent imaging biomarker imaging potential imaging study in vivo in vivo imaging kinetic model longitudinal positron emission tomography male mild cognitive impairment mind control neuroimaging neuropathology nonhuman primate novel pre-clinical prevent prodromal Alzheimer&apos s disease radioligand radiotracer sex tau Proteins tau-1 tool uptake volunteer

项目摘要

Project Summary/Abstract Microtubule (MT) integrity is critical for cell function and viability. Its disruption in Alzheimer’s disease (AD) is commonly attributed to hyperphosphorylation of the MT-associated protein, tau. However, the time course of MT instability in neurodegenerative cascade of the disease progression remains unknown. In vivo MT imaging offers an opportunity to gain this critical information on MT changes in relation to staging of AD. As MT destabilization is a common factor in both Aβ and tau-based AD pathologies, we hypothesize that a targeted MT PET radiotracer can be used as an early indicator of neuronal health and brain functions prior to onset of AD symptoms. Our lab reported the first brain-penetrant MT PET ligand, [11C]MPC-6827, and evaluated its imaging potential in vivo in rodent and non-human primate (NHP) models of AD. We evaluated its safety and radiation dosimetry profile in six healthy male and female volunteers and its imaging efficacy in two cognitively normal and two impaired older adults. Our mechanistic studies showed that [11C]MPC-6827 is selective for destabilized tubulins, and uptake increases with Aβ/tau burden in AD brain. The proposed trial will the first to measure the efficacy of an MT-based PET ligand as an early imaging biomarker in cognitively normal and mildly cognitively impaired/early AD subjects. We propose to conduct a clinical PET imaging study of [11C]MPC-6827. In Aim 1, we will determine the metabolic, pharmacokinetic, and imaging distribution parameters of [11C]MPC-6827 in three groups (n=75, 25/group) of participants, to be enrolled from the Wake Forest AD Research Center: 1) cognitively normal adults who are amyloid PET negative; 2) cognitively normal adults who are amyloid PET positive; and 3) adults with MCI or early AD who are amyloid PET positive. All the groups will be matched for age and sex. In Aim 2, [11C]MPC-6827 imaging parameters will be compared among the three groups and correlated with individual amyloid and tau PET measures, cerebrospinal fluid (CSF) measures, age, and cognitive scores. In Aim 3, we will perform longitudinal PET/CT scans with [11C]MPC-6827 in all the subjects (n=25/group) from Aim 1, 24 months after their first scan. Relationship of MT destabilization and disease progression will be established by correlating the radiotracer uptake with their associated amyloid and tau burdens. All the imaging analyses will be performed blinded to subject diagnosis. This study will provide rich imaging data source to validate MT destabilizations as an early neurodegenerative biomarker for AD pathogenesis.

项目概要/摘要微管 (MT) 完整性对于阿尔茨海默病中的细胞功能和活力至关重要。 (AD) 通常归因于 MT 相关蛋白 tau 的过度磷酸化。 MT 不稳定在疾病进展的神经退行性级联中的过程仍然未知。成像提供了获得与 AD 分期相关的 MT 变化的关键信息的机会。不稳定是基于 Aβ 和 tau 的 AD 病理学的常见因素，我们发现靶向 MT PET 放射性示踪剂可用作 AD 发病前神经健康和大脑功能的早期指标我们的实验室报告了第一个脑渗透性 MT PET 配体 [11C]MPC-6827，并对其成像进行了评估。我们评估了其在 AD 啮齿动物和非人类灵长类动物 (NHP) 模型中的体内潜力。六名健康男性和女性志愿者的剂量测定曲线及其对两名认知正常和我们的机制研究表明，[11C]MPC-6827 对不稳定的老年人具有选择性。 AD 大脑中微管蛋白的含量随 Aβ/tau 负荷的增加而增加。基于 MT 的 PET 配体作为早期成像生物标志物在认知正常和轻度认知障碍中的功效受损/早期 AD 受试者。我们建议对 [11C]MPC-6827 进行临床 PET 成像研究，在目标 1 中，我们将确定。 [11C]MPC-6827 在三组中的代谢、药代动力学和成像分布参数（n=75， 25 名/组）参与者，从维克森林 AD 研究中心招募：1）认知正常淀粉样蛋白 PET 阴性的成年人；2) 淀粉样蛋白 PET 阳性的认知正常成年人；以及 3) 淀粉样蛋白 PET 阳性的成年人；淀粉样蛋白 PET 呈阳性的 MCI 或早期 AD 所有组都将在年龄和性别上进行匹配。 [11C]MPC-6827 成像参数将在三组之间进行比较，并与个体相关在目标 3 中，我们进行了淀粉样蛋白和 tau PET 测量、脑脊液 (CSF) 测量、年龄和认知评分。将使用 [11C]MPC-6827 对目标 1、24 的所有受试者（n=25/组）进行纵向 PET/CT 扫描第一次扫描后几个月，将确定 MT 不稳定与疾病进展的关系。将放射性示踪剂的摄取与其相关的淀粉样蛋白和 tau 蛋白负荷关联起来。本研究将提供丰富的影像数据源来验证 MT。不稳定作为 AD 发病机制的早期神经退行性生物标志物。