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

项目 2 - 将小胶质细胞激活与血脑屏障完整性和神经认知功能相关联

• 批准号: 10024602
• 负责人: MEGGAN MACKAY
• 金额: $ 66.25万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10024602
• 关键词: Adult; Affect; Anatomy; Antibodies; Antibody titer measurement; Area; Assessment tool; Benzodiazepine Receptor; Blood; Blood - brain barrier anatomy; Brain; Brain imaging; Brain region; Chronic; Clinical; Cognition; Cognitive; Cognitive deficits; Communities; DNA receptor; Data; Descriptor; Development; Diagnostic; Diffusion Magnetic Resonance Imaging; Disease; Disease Marker; Exhibits; Exposure to; Fc Receptor; Functional Magnetic Resonance Imaging; Funding; Gadolinium; Hippocampus (Brain); Human; Image; Imaging Device; Impaired cognition; Impairment; Individual; Inflammatory; Investigation; Ionizing radiation; Ligand Binding; Logistics; Long-Term Effects; Lupus; Magnetic Resonance; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Metabolic; Metabolism; Methods; Microglia; Molecular; Multimodal Imaging; Mus; N-Methyl-D-Aspartate Receptors; Neurocognitive; Pathogenicity; Pathologic; Pathway interactions; Patients; Performance; Peripheral; Positron-Emission Tomography; Process; Proxy; Psychometrics; Radiation; Reporting; Reproducibility; Research Design; Rest; Role; Scanning; Serological; Serum; Spin Labels; Structure; Synapses; Systemic Lupus Erythematosus; Testing; Therapeutic; Time; Tracer; base; blood-brain barrier permeabilization; brain abnormalities; brain dysfunction; cognitive function; cognitive testing; contrast enhanced; disabling disease; fetal; fluorodeoxyglucose positron emission tomography; healthy volunteer; imaging approach; imaging biomarker; imaging modality; imaging study; improved; in vivo; individual patient; insight; instrumentation; intravenous injection; longitudinal design; mouse model; multimodality; neuroinflammation; neuron loss; neurotoxic; neurotoxicity; neurotransmission; non-invasive imaging; novel; radiotracer; response; spatial memory; synaptic function; synaptic pruning; targeted biomarker; treatment strategy; uptake; white matter; white matter change

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.

项目：2摘要/摘要 项目2继续关注人类SLE中的脑成像研究以研究认知机制 这种疾病患者的功能障碍。拟议的研究利用了最后的信息 资金周期：静息代谢活动中存在一致的升高（局部突触的代理 功能）在SLE患者的海马中，与抗DNA受体抗体（DNRAB）滴度相关 并具有认知测试电池的性能。在下一个资金周期中，我们计划使用多模式宠物和 MRI成像工具确定该疾病认知功能障碍的机理基础。新的 项目1的实验证据暗示了海马神经毒性中的小胶质细胞（MG）激活 对DNRAB的反应。因此，我们将使用[11C] -PBR28 PET评估SLE患者的这种现象 与健康的志愿者相比。为此，将在海马中量化放射性示意剂的摄取 以及其他代谢活跃的与SLE相关的大脑区域。使用纵向设计，我们将评估区域 MG在两年内激活，并确定这些变化与同时评估有关 认知功能，DNRAB滴度和在同一受试者中测得的静息代谢活性。同样地， 我们将使用定量MRI方法来评估海马中的BBB渗透性 与SLE相关的大脑区域。该措施的变化将与并发的血清学和 认知评估以及基本疾病过程的其他成像描述符。这 但是，由于某些成像的侵入性，这种方法的广泛适用性可能受到限制 方法。为了使这些评估在临床上更容易访问，我们将探索使用新的非 - 侵入性成像工具作为替代性疾病标记。总而言之，多模式成像方法 项目2将为评估SLE-CI的新治疗策略提供客观指标。