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

项目：2 总结/摘要 项目 2 继续关注人类 SLE 的脑成像研究，以研究认知机制 患有这种疾病的患者的功能障碍。拟议的研究利用了过去获得的信息 资金周期：静息代谢活动持续升高（局部突触的代表） SLE 患者海马中的功能），其与抗 DNA 受体抗体（DNRAb）滴度相关 以及认知测试电池的性能。在下一个融资周期中，我们计划使用多模式 PET 和 MRI 成像工具可确定这种疾病认知功能障碍的机制基础。新 项目 1 的实验证据表明小胶质细胞 (MG) 激活与海马神经毒性有关 对 DNRAb 的反应。因此，我们将使用 [11C]-PBR28 PET 来评估 SLE 患者的这种现象 与健康志愿者受试者相比。为此，将量化海马体中放射性示踪剂的吸收 以及其他代谢活跃的 SLE 相关大脑区域。使用纵向设计，我们将评估区域 两年期间的 MG 激活，并确定这些变化与同时评估的关系 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 方法来评估海马体和其他部位的 BBB 通透性 SLE 相关的大脑区域。该措施的变化将类似地与同时发生的血清学和 认知评估以及潜在疾病过程的其他影像描述符。的 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。为了使这些评估在临床上更容易进行，我们最后将探索使用更新的非 侵入性成像工具作为替代疾病标志物。综上所述，多模态成像方法 项目 2 将为评估 SLE-CI 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.