PET imaging of microtubules in cognitively normal and impaired older adults

项目摘要/摘要 微管(MT)的完整性对细胞的功能和活性至关重要。它在阿尔茨海默病中的破坏作用 (AD)通常归因于MT相关蛋白tau的过度磷酸化。然而，时间 在疾病进展的神经退行性级联中，MT不稳定的过程仍不清楚。体内移植 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。作为MT 不稳定是Aβ和基于tau的AD病理中的共同因素，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性MT PET配体[11C]MPC-6827，并对其成像进行了评价 在啮齿动物和非人灵长类(NHP)AD模型中的体内潜力。我们评估了它的安全性和辐射性。 6名健康男性和女性志愿者的剂量学分布及其在两名认知正常和健康女性中的成像效果 两个身体受损的老年人。我们的机理研究表明，[11C]MPC-6827对不稳定具有选择性 在AD脑中，微管蛋白和摄取随着β/tau负荷的增加而增加。拟议中的试验将是第一个衡量 以MT为基础的PET配体在认知正常和轻度认知中作为早期成像生物标志物的有效性 AD受损/早期受试者。 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(n=75， 25名/组)参与者，从维克森林AD研究中心登记：1)认知正常 淀粉样蛋白PET阴性的成年人；2)认知正常的淀粉样蛋白PET阳性的成年人；以及3)成年人 淀粉样蛋白PET阳性的MCI或早期AD患者。所有的群体都将在年龄和性别上进行匹配。在目标2中， [11C]将MPC-6827成像参数在三组间进行比较，并与个体进行对比 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 在他们第一次扫描后的几个月。MT不稳定与疾病进展的关系将通过以下方式建立 放射性示踪剂摄取与其相关的淀粉样蛋白和tau负荷的相关性。所有的成像分析都会 对受试者诊断盲目执行。本研究将为MT的验证提供丰富的影像数据来源 作为阿尔茨海默病发病机制的早期神经退行性生物标志物的失稳。

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.