Longitudinal Imaging Biomarkers of Prodromal DLB

项目摘要/摘要 具有路易体痴呆核心临床特征的轻度认知障碍(MCI)被认为是 作为DLB的前驱阶段(MCI-LB期)。MCI-LB型患者经常进展为DLB型，但亚型可能 有一系列额外的AD病理。蛋白质特异性疾病发展的快速进展- 修改疗法突显了MCI-LB对生物标记物的迫切需求，因为临床试验将需要 有足够的能量在前驱阶段检测疾病进展的变化，当疾病- 修改疗法将是最有效的。在这个项目的最初周期中，我们确定了交叉- 经病理证实的DLB断面和纵向成像生物标志物。当前的经济周期 U01项目旨在识别前驱DLb的横断面和纵向多峰生物标志物 并准备进行蛋白质特异性疾病修改的临床试验，这些临床试验将需要这些生物标志物来 选择参与者并跟踪MCI-LB的结果。多模式生物标志物方法的基本原理 起源于多因素并存的LBD和AD病理，在DLB和MCI-LBD中类似。我们会 确定横断面和纵向PET、SPECT、MRI和多导睡眠图(PSG)生物标志物 MCI-LB与认知正常对照进行比较。我们还将确定年龄、性别作为生物学指标 变量、载脂蛋白ε4状态和磁共振成像上的脑血管病变调节了这些差异。在试行中 分析，我们将比较蛋白质错误折叠循环放大(PMCA)和实时抖动诱导 检测脑脊液中α-突触核蛋白的转换(RT-QuIC)以鉴别微血管内皮细胞白血病与对照组。最后，我们会 将我们的发现与病理结果相关联。将MCI-LB型患者纳入当前周期将基于 根据DLB的一个或多个核心临床特征，而不是基于生物标志物的发现。这将提供 有机会验证建议的和新的生物标记物在MCI-LB诊断中的使用以及 确定哪些生物标记物可以预测从MCI-LB到DLB的进展。所有样本、临床、成像和 将根据帕金森氏症收集和分享来自MCI-LB病例和对照的尸检数据 疾病生物标志物计划指南。

PROJECT SUMMARY / ABSTRACT Mild Cognitive Impairment (MCI) with core clinical features of dementia with Lewy bodies (DLB) is recognized as the prodromal stage of DLB (MCI-LB). Patients with MCI-LB frequently progress to DLB, but a subset may have a range of additional AD pathology. Rapid advances in the development of protein-specific disease- modifying therapies highlight a critical need for biomarkers in MCI-LB, because clinical trials will need to be sufficiently powered to detect changes in disease progression during the prodromal phase, when the disease- modifying therapies would be most effective. During the initial cycle of this project, we determined the cross- sectional and longitudinal imaging biomarkers of DLB with pathologic confirmation. The current cycle of the U01 project is designed to identify cross-sectional and longitudinal multi-modal biomarkers of prodromal DLB in MCI-LB, and prepare for protein-specific disease-modifying clinical trials that will need these biomarkers for selection of participants and to track outcomes in MCI-LB. The rationale for a multi-modal biomarker approach stems from the multi-factorial and co-existing LBD and AD pathology in DLB and similarly in MCI-LB. We will determine the cross-sectional and longitudinal PET, SPECT, MRI, and polysomnogram (PSG) biomarkers of MCI-LB compared to cognitively unimpaired controls. We will also determine whether age, sex as a biological variable, APOE ε4 status, and cerebrovascular disease lesions on MRI modulate these differences. In a pilot analysis, we will compare protein misfolding cyclic amplification (PMCA) and real-time quaking-induced conversion (RT-QuIC) assays for α-synuclein in CSF for differentiating MCI-LB from controls. Finally, we will correlate our findings with pathologic outcomes. Inclusion of MCI-LB patients in the current cycle will be based on the presence of one or more core clinical features of DLB and not on biomarker findings. This will provide the opportunity to validate the use of proposed and novel biomarkers in the diagnosis of MCI-LB and to determine which biomarkers predict progression from MCI-LB to DLB. All samples, clinical, imaging, and autopsy data from MCI-LB cases and controls will be collected and shared according to the Parkinson's Disease Biomarkers Program guidelines.