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: 9894894
• 负责人: Keith A Josephs
• 金额: $ 76.33万
• 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/9894894
• 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.

项目概要 进行性核上性麻痹 (PSP) 是一种破坏性神经退行性疾病，其特征是 4-重复 (4R) tau 蛋白在大脑中沉积。患者通常会出现姿势不稳的症状 跌倒、轴性强直和垂直核上性凝视麻痹，尽管其他非典型临床综合征也发生在 哪些患者出现帕金森症、步态冻结、行为异常、肢体失用或言语 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 tau-PET 配体 [18F]AV-1451 在 PSP 中的行为，并表明它与其他神经影像学相关 神经退行性变的措施。第一个周期重点关注 PSP 的典型临床表现。自1日起 周期中，一个领先的专家小组发布了新的标准，其中包括诊断非典型临床的标准 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 因此，第二个周期的目标是表征临床、神经影像学和神经病理学 典型和非典型 PSP 综合征的特征。具体来说，我们的目标是表征交叉 PSP 综合征的截面和纵向多模态神经影像特征，确定 神经影像学与临床进化的关系，并评估 PSP 的尸检特征 综合症。我们将获得 160 名 PSP 患者的数据，以便我们能够实现我们的目标（第一批招募了 84 名患者） 周期和第二周期将招募 76 名）。每个新招募的患者都将接受相同的治疗 对第一个周期的 84 名患者进行的检查，包括神经学和吞咽困难评估、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 配体的 PET。所有患者将接受两次相隔一年的系列评估。我们将 主要评估 PSP 综合征所有三种神经影像学模式的差异和共性 使用聚焦感兴趣区域的方法，该方法将针对关键的脑干、皮质下和皮质区域 涉及 PSP 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来评估跨领域的模式 整个大脑。临床演变（包括吞咽困难的演变）与 PSP 之间的关系 将评估综合征和神经影像学测量。将对所有尸体进行尸检 两个周期中死亡的患者和 4R tau 负荷将在 PSP 综合征之间进行比较。我们也会 确定不同综合征之间神经影像学差异与 tau 蛋白负荷相关的程度 研究其他病理如何与不同综合征相关。这笔赠款的结果将 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至关重要，这将有助于诊断、跟踪疾病 进展并允许患有所有 PSP 综合征的患者参与未来的治疗试验。