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

基本信息

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
项目类别：
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

项目摘要

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 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。新的项目 1 的实验证据表明海马神经毒性中小胶质细胞 (MG) 的激活对 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。同样地，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。这然而，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。