Longitudinal multi-modal imaging in progressive supranuclear palsy syndromes

进行性核上性麻痹综合征的纵向多模态成像

• 批准号: 10266026
• 负责人: Keith A Josephs
• 金额: $ 77.93万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10266026
• 关键词: Address; Anatomy; Apraxias; Atrophic; Autopsy; Behavior; Behavioral; Biological Markers; Brain; Brain Stem; Brain imaging; Brain region; Characteristics; Classification; Clinical; Data; Deglutition Disorders; Deposition; Development; Diagnosis; Diffusion Magnetic Resonance Imaging; Disease; Disease Progression; Evaluation; Evolution; Exhibits; Freezing; Future; Gait; Goals; Grant; Heterogeneity; Impairment; Knowledge; Language; Lead; Ligands; Limb structure; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Modality; Modeling; Monitor; Movement Disorders; Multimodal Imaging; Nerve Degeneration; Neurobiology; Neurodegenerative Disorders; Neurologic; Parkinsonian Disorders; Pathologic; Pathology; Patient Recruitments; Patients; Pattern; Positron-Emission Tomography; Progressive Supranuclear Palsy; Proteins; Publishing; Research; Research Personnel; Societies; Speech; Standardization; Structure; Symptoms; Syndrome; Time; Variant; Work; brain tissue; experience; falls; gaze palsy; improved; indexing; interest; multimodality; neurobiological mechanism; neuroimaging; oculomotor; posture instability; prognostic; rate of change; recruit; relating to nervous system; research study; tau Proteins; tau mutation; treatment effect; treatment trial; uptake; white matter

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.

项目摘要 进行性核上麻痹（PSP）是一种毁灭性神经退行性疾病，其特征是 蛋白质4重复（4R）tau在大脑中的沉积。患者通常存在姿势不稳定 跌落，轴向刚度和垂直上近视凝视麻痹，尽管其他非典型临床综合症发生在 哪些患者出现帕金森氏症，步态冻结，行为异常，四肢失败或语音 和语言困难。在R01的第一个周期中，我们表征了横截面和纵向 PSP中Tau-pet配体[18F] AV-1451的行为，并表明它与其他神经成像有关 神经退行性的度量。第一个周期的重点是PSP的典型临床表现。自第一个 循环专家小组发表了新标准，标准诊断了非典型临床 综合征。目前，我们缺乏对非典型PSP综合征的神经生物学的了解。主要 因此，第二周期的目标是表征临床，神经影像学和神经病理学的目标 跨典型和非典型PSP综合征的特征。具体而言，我们旨在表征交叉 PSP综合征的分段和纵向多模式神经影像学特征，确定 神经影像学与临床进化之间的关系，并评估PSP的尸检特征 综合征。我们将获得来自160名PSP患者的数据，使我们能够解决我们的目标 周期和76个将在第二周期中招募）。每个新招募的患者都会经历相同的 考试作为第一个周期的84例患者，包括神经系统和吞咽困难，3T 磁共振成像（MRI），包括结构MRI和扩散张量成像（DTI）和TAU- 使用[18F] AV-1451配体的PET。所有患者将进行两次连续评估一年。我们将 评估PSP综合征的所有三种神经影像模式的差异和共同点 使用重点利益区域的方法，该方法将针对关键的脑干，皮层和皮质区域 与PSP有关的。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。还将进行体素级分析以评估跨越的模式 整个大脑。临床演化之间的关系，包括吞咽困难的演变和PSP 将评估综合征和神经成像措施。将对所有检查进行尸检检查 在PSP综合征中将比较来自死亡和4R tau负担的周期的患者。我们也会 确定综合症之间的神经影像学差异与tau负担有关的程度 研究其他病理如何与不同的综合症相关。这笔赠款的结果将 提高我们对PSP临床和解剖异质性的神经基础的了解 对于将有助于诊断的PSP的最佳生物标志物的开发也将是必不可少的 进展并允许所有PSP综合症患者纳入以后的治疗试验中。