Project 2- Correlating microglial activation with blood brain barrier integrity and neurocognitive performance

项目：2摘要/摘要 项目2继续关注人类系统性红斑狼疮的脑成像研究，以探索认知机制。 这种疾病患者的功能障碍。拟议的研究利用了上一次研究中获得的信息。 资金周期：静息代谢活动持续升高(局部突触的替代指标 与抗DNA受体抗体(DNRAb)效价相关 以及在认知测试电池上的表现。在下一个资金周期中，我们计划使用多式联运PET和 核磁共振成像工具，以确定该障碍的认知功能障碍的机制基础。新的 项目1的实验证据表明，小胶质细胞(MG)在海马神经毒性中激活 对DNRAb的回应。因此，我们将使用[11C]-PBR28 PET来评估SLE患者的这种现象 与健康的志愿者对象进行比较。为此，将在海马体中量化放射性示踪剂的摄取 以及其他与系统性红斑狼疮相关的代谢活跃的脑区。使用纵向设计，我们将评估区域 在两年内激活MG，并确定这些变化与并发评估的关系 在同一受试者中测量认知功能、DNRAb滴度和静息代谢活动。同样， 我们将使用定量mri方法来评估海马区和其他脑区的血脑屏障通透性。 系统性红斑狼疮相关脑区。这项指标的变化将同样与同时进行的血清学和 认知评估，以及潜在疾病过程的其他成像描述。这个 然而，这种方法的广泛适用性可能会受到一些成像的侵入性的限制 方法：研究方法。为了使这些评估更容易在临床上使用，我们最后将探索使用更新的非 作为替代疾病标志物的侵入性成像工具。总而言之，多模式成像方法在 项目2将为评估SLE-CI的新治疗策略提供客观指标。

Project: 2 Summary/Abstract Project 2 continues our focus on brain imaging studies in human SLE to investigate mechanisms of cognitive dysfunction in patients with this disorder. The proposed study leverages the information gained in the last funding cycle: the presence of consistent elevations in resting metabolic activity (a proxy for local synaptic function) in the hippocampus of SLE patients, which correlated with anti DNA receptor antibody (DNRAb) titers and with performance on cognitive test battery. In the next funding cycle, we plan to use multimodal PET and MRI imaging tools to determine the mechanistic basis for cognitive dysfunction in this disorder. New experimental evidence from Project 1 implicates microglial (MG) activation in the hippocampal neurotoxic response to DNRAb. We will therefore use [11C]-PBR28 PET to assess this phenomenon in SLE patients compared to healthy volunteer subjects. To this end, radiotracer uptake will be quantified in the hippocampus and other metabolically active SLE-related brain regions. Using a longitudinal design, we will evaluate regional MG activation over a two-year period, and determine how these changes relate to concurrent assessments of cognitive functioning, DNRAb titers, and resting metabolic activity measured in the same subjects. Likewise, we will use a quantitative MRI approach to evaluate BBB permeability in the hippocampus and in the other SLE-related brain regions. Changes in this measure will similarly be compared with concurrent serological and cognitive assessments, as well as with the other imaging descriptors of the underlying disease process. The broad applicability of this approach may be limited, however, by the invasiveness of some of the imaging methods. To make these assessments more clinically accessible, we will lastly explore the use of newer non- invasive imaging tools as alternative disease markers. In summary, the multimodal imaging approach in Project 2 will provide objective metrics for the assessment of new treatment strategies for SLE-CI.