Longitudinal multi-modal imaging in progressive supranuclear palsy syndromes

项目总结 进行性核上性麻痹(PSP)是一种破坏性的神经退行性疾病，其特征是 4-重复(4R)tau蛋白在大脑中的沉积。患者通常表现为姿势不稳定， 跌倒、轴向僵直和垂直核上凝视麻痹，尽管其他非典型临床症状也出现在 哪些患者有帕金森氏症、步态僵硬、行为异常、肢体失用或言语障碍 和语言障碍。在R01的第一个循环中，我们表征了横截面和纵向 Tau-PET配体[18F]AV-1451在PSP中的行为及其与其他神经影像的关系 神经退行性变的测量。第一个周期集中于PSP的典型临床表现。从1日起 周期，一个主要专家小组发布了新的标准来诊断非典型临床 综合症。我们目前对非典型PSP综合征的神经生物学缺乏了解。初级阶段 因此，第二周期的目标是描述临床、神经影像和神经病理学的特征。 典型和非典型PSP综合征的特征。具体地说，我们的目标是描述这种交叉- PSP综合征的横断面和纵向多模式神经影像特征决定了 神经影像与临床演变的关系及对PSP尸检特点的评价 综合症。我们将有来自160名PSP患者的数据，以使我们能够实现我们的目标(84名招募到第一 将在第二个周期征聘的76人)。每个新招募的患者都将接受相同的 第一个周期的84名患者进行了检查，包括神经系统和吞咽困难的评估，3T 磁共振成像(MRI)，包括结构MRI和扩散张量成像(DTI)，以及tau- 使用[18F]AV-1451配基的pET。所有患者将每隔一年接受两次系列评估。我们会 主要评估所有三种神经影像检查在PSP综合征中的差异和共性 使用聚焦感兴趣区的方法，该方法将针对关键的脑干、皮质下和皮质区域 参与PSP的人。然后我们将确定PSP综合征是否表现出独特的多模式 使用分类模型的签名。还将执行体素级别分析，以评估 整个大脑。包括吞咽困难在内的临床演变与PSP的关系 将对症状和神经成像措施进行评估。将对所有人进行尸检 来自两个周期的死亡和4R tau负荷的患者将在PSP综合征中进行比较。我们还将 确定不同症状的神经影像差异与tau负荷和 研究其他病理因素如何与不同的证候相关联。这笔赠款的结果将是 增加我们对PSP临床和解剖异质性的神经基础的了解 对于开发PSP的最佳生物标志物也是必不可少的，这将有助于疾病的诊断、跟踪 进展，并允许所有PSP综合征的患者纳入未来的治疗试验。

PROJECT SUMMARY Progressive supranuclear palsy (PSP) is a devastating neurodegenerative disorder that is characterized by deposition of the protein 4-repeat (4R) tau in the brain. Patients typically present with postural instability with falls, axial rigidity and vertical supranuclear gaze palsy, although other atypical clinical syndromes occur in which patients present with parkinsonism, freezing of gait, behavioral abnormalities, limb apraxia or speech and language difficulties. In the 1st cycle of the R01 we characterized the cross-sectional and longitudinal behavior of the tau-PET ligand [18F]AV-1451 in PSP and showed that it is related to other neuroimaging measures of neurodegeneration. The 1st cycle focused on the typical clinical presentation of PSP. Since the 1st cycle, a panel of leading experts published new criteria with a standard to diagnose the atypical clinical syndromes. We currently lack understanding of the neurobiology of the atypical PSP syndromes. The primary goal of the 2nd cycle is, therefore, to characterize the clinical, neuroimaging and neuropathological features across typical and atypical PSP syndromes. Specifically, we aim to characterize the cross- sectional and longitudinal multi-modal neuroimaging signatures of the PSP syndromes, determine the relationship between neuroimaging and clinical evolution, and evaluate the autopsy characteristics of the PSP syndromes. We will have data from 160 PSP patients to allow us to address our aims (84 recruited into the 1st cycle and 76 which will be recruited in the 2nd cycle). Each newly recruited patient will undergo the identical examinations as the 84 patients from the 1st cycle, including a neurological and dysphagia evaluation, a 3T magnetic resonance imaging (MRI) that includes structural MRI and diffusion tensor imaging (DTI), and tau- PET using the [18F]AV-1451 ligand. All patients will undergo two serial assessments one year apart. We will assess differences and commonalities in all three neuroimaging modalities across PSP syndromes primarily using a focused region-of-interest approach which will target key brainstem, subcortical and cortical regions that are involved in PSP. We will then ascertain whether the PSP syndromes exhibit unique multi-modal signatures using a classification model. Voxel-level analyses will also be performed to assess patterns across the whole brain. The relationship between clinical evolution, including the evolution of dysphagia, and the PSP syndromes and neuroimaging measures will be assessed. Autopsy examinations will be performed on all patients from both cycles that die and 4R tau burden will be compared across PSP syndromes. We will also determine the degree to which neuroimaging differences across syndromes are related to tau burden and investigate how additional pathologies are associated with the different syndromes. The results of this grant will increase our knowledge of the neural underpinnings of the clinical and anatomical heterogeneity in PSP and will also be essential for the development of optimum biomarkers for PSP that will aid diagnosis, track disease progression and allow patients with all PSP syndromes to be included in future treatment trials.