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

• 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
• 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' s Disease; Alzheimer' s disease brain; Alzheimer' s disease diagnosis; Alzheimer' s disease model; Alzheimer' 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' s disease; radioligand; radiotracer; sex; tau Proteins; tau-1; tool; uptake; volunteer

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.

项目总结/摘要 微管（MT）的完整性对细胞功能和活力至关重要。它对阿尔茨海默病的破坏 (AD)通常归因于MT相关蛋白tau的过度磷酸化。然而时过境迁 在疾病进展的神经退行性级联反应中MT不稳定的过程仍然未知。体内MT 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。稳如泰山 不稳定是Aβ和tau蛋白为基础的AD病理学的共同因素，我们假设靶向MT PET放射性示踪剂可作为AD发病前神经元健康和脑功能的早期指标 症状本实验室报道了第一个脑穿透MT PET配体，[11 C]MPC-6827，并对其成像进行了评价 在啮齿动物和非人灵长类动物（NHP）AD模型中的体内潜力。我们评估了它的安全性和辐射 在6名健康男性和女性志愿者中的剂量学特征及其在2名认知正常和 两个残疾老人我们的机制研究表明，[11 C]MPC-6827对去稳定的 微管蛋白，并且摄取随着AD脑中Aβ/tau负荷而增加。拟议中的试验将是第一个衡量 基于MT的PET配体作为认知正常和轻度认知患者早期成像生物标志物的功效 受损/早期AD受试者 我们建议对[11 C]MPC-6827进行临床PET成像研究。在目标1中，我们将确定 [11 C]MPC-6827在三组中的代谢、药代动力学和成像分布参数（n=75， 从维克森林AD研究中心招募的参与者：1）认知正常 淀粉样蛋白PET阴性的成年人; 2）淀粉样蛋白PET阳性的认知正常的成年人;和3）成年人 患有MCI或早期AD的患者，淀粉样蛋白PET阳性。所有的组将在年龄和性别上相匹配。在目标2中， [11 C]MPC-6827成像参数将在三组之间进行比较，并与个体相关 淀粉样蛋白和tau PET测量、脑脊液（CSF）测量、年龄和认知评分。在目标3中，我们 将对目标1、24中的所有受试者（n=25/组）进行[11 C]MPC-6827纵向PET/CT扫描 在第一次扫描后几个月。MT不稳定和疾病进展的关系将通过以下方式建立： 将放射性示踪剂摄取与其相关的淀粉样蛋白和tau负荷相关联。所有的影像分析 对受试者诊断设盲。本研究将为验证MT提供丰富的成像数据源 不稳定作为AD发病机制的早期神经退行性生物标志物。