Imaging antibody effects in SLE patients

成像抗体对 SLE 患者的影响

• 批准号: 8741188
• 负责人: MEGGAN MACKAY
• 金额: $ 57.53万
• 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 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8741188
• 关键词: Adult; Animals; Antibodies; Area; Autoantibodies; Behavior; Behavioral; Binding; Biological Markers; Biology; Blood - brain barrier anatomy; Brain; Brain Injuries; Central Nervous System Diseases; Clinical Trials; Cognition; Cognitive; Complement; Cross-Sectional Studies; Development; Diagnostic; Disease Progression; Glutamate Receptor; Glutamates; Goals; Grant; Hippocampus (Brain); Human; Image; Imaging Techniques; Immune; Impaired cognition; Individual; Ligands; Longitudinal Studies; Lupus; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Memory; Memory impairment; Metabolic; Metabolism; Metric; Molecular; Mus; N-Methyl-D-Aspartate Receptors; Nervous System Trauma; Neuraxis; Neurons; Neuropsychological Tests; Pathologic; Patients; Permeability; Positron-Emission Tomography; Predictive Value; Prevalence; Process; Productivity; Quality of life; Receptor Activation; Recording of previous events; Reporting; Research; Rest; Role; Scientist; Serum; Societies; Syndrome; Systemic Lupus Erythematosus; Testing; Therapeutic; Time; Tissues; Toxic effect; abstracting; base; behavior test; behavioral impairment; brain metabolism; cohort; fetal; fluorodeoxyglucose positron emission tomography; functional status; glucose metabolism; human subject; improved; longitudinal analysis; mouse model; neuroprotection; neuropsychiatry; neuropsychological; novel; programs; time use; Adult; Animals; Antibodies; Area; Autoantibodies; Behavior; Behavioral; Binding; Biological Markers; Biology; Blood - brain barrier anatomy; Brain; Brain Injuries; Central Nervous System Diseases; Clinical Trials; Cognition; Cognitive; Complement; Cross-Sectional Studies; Development; Diagnostic; Disease Progression; Glutamate Receptor; Glutamates; Goals; Grant; Hippocampus (Brain); Human; Image; Imaging Techniques; Immune; Impaired cognition; Individual; Ligands; Longitudinal Studies; Lupus; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Memory; Memory impairment; Metabolic; Metabolism; Metric; Molecular; Mus; N-Methyl-D-Aspartate Receptors; Nervous System Trauma; Neuraxis; Neurons; Neuropsychological Tests; Pathologic; Patients; Permeability; Positron-Emission Tomography; Predictive Value; Prevalence; Process; Productivity; Quality of life; Receptor Activation; Recording of previous events; Reporting; Research; Rest; Role; Scientist; Serum; Societies; Syndrome; Systemic Lupus Erythematosus; Testing; Therapeutic; Time; Tissues; Toxic effect; abstracting; base; behavior test; behavioral impairment; brain metabolism; cohort; fetal; fluorodeoxyglucose positron emission tomography; functional status; glucose metabolism; human subject; improved; longitudinal analysis; mouse model; neuroprotection; neuropsychiatry; neuropsychological; novel; programs; time use

PROJECT SUMMARY/ABSTRACT - PROJECT 2 Reported prevalence of cognitive impairment in SLE ranges from 30-80% and behavioral alterations range from 17-75% with significant effects on quality of life and individual productivity. A hypothesis of this Program Grant is that autoantibodies cross-reactive with dsDNA and NMDA receptors, DNRAbs, contribute to cognitive and behavioral impairment in SLE patients. The goals of Project 2 are to continue development of FDG-PET as a biomarker for cognitive and behavioral impairment in NPSLE and to utilize other novel imaging techniques to enhance our understanding of pathologic mechanisms related to DNRAb effects on the brain. Cross-sectional FDG-PET studies of resting brain glucose metabolism demonstrate abnormal hypermetabolism in the hippocampus of SLE subjects. Hippocampus hypermetabolism and elevated serum titers of DNRAb combined have a higher predictive value for memory impairment than either variable alone. This is the first example of a consistent and robust imaging finding that reflects both impaired functional status and a proposed pathogenic mechanism in NPSLE. The longitudinal study proposed in Project 2 will validate and extend these associations. Subjects in the SLE cohort will be selected to have a range of serum DNRAb titers that is equally distributed across a spectrum of normal to high titers. The proposed longitudinal study will inform us about correlates of cognitive and behavioral change over time using FDG-PET imaging (Aim 1). Additionally, we will explore NMDAR biology in human subjects with a novel PET ligand, [11C]-CNS5161, used to localize and quantify NMDAR activation (Aim 2) and explore the role of blood brain barrier (BBB) integrity in cognitive and behavioral impairment (Aim 3). These studies complement the studies proposed in Project 1 that will explore the molecular and cellular basis for the hippocampal hypermetabolism in mouse models where tissue is readily available. In conducting these longitudinal studies, we will also determine the best biomarker with sensitivity for disease progression that can be used as a metric for a clinical trial.

项目摘要/摘要 - 项目2 报告的SLE认知障碍的患病率在30-80％和行为范围内 改变的范围为17-75％，对生活质量和个人的影响很大 生产率。该计划赠款的一个假设是自动抗体与 DSDNA和NMDA受体，DNRABS，有助于认知和行为障碍 SLE患者。项目2的目标是继续开发FDG-PET作为生物标志物 用于NPSLE中的认知和行为障碍，并利用其他新型成像技术 为了增强我们对与DNRAB对大脑作用相关的病理机制的理解。 静止脑葡萄糖代谢的横截面FDG-PET研究表明异常 SLE受试者海马中的超定代谢。海马多代谢和 DNRAB合并的升高血清滴度具有更高的记忆预测值 损害比单独的变量。这是一个一致且坚固的一个例子 成像发现反映了功能状况受损和提出的致病性 NPSLE机制。项目2中提出的纵向研究将验证和扩展 这些关联。 SLE队列中的受试者将被选为一系列血清 dnrab滴度平均分布在正常滴度到高滴度的频谱上。提议 纵向研究将随着时间的推移告知我们认知和行为改变的相关性 使用FDG-PET成像（AIM 1）。此外，我们将探索人类的NMDAR生物学 具有新型宠物配体的受试者[11C] -CNS5161，用于本地化和量化NMDAR 激活（AIM 2）并探讨血脑屏障（BBB）完整性在认知和 行为障碍（目标3）。这些研究补充了项目1中提出的研究 这将探索小鼠海马多代谢的分子和细胞基础 易于使用的模型。在进行这些纵向研究时，我们也将 确定最佳的生物标志物，对疾病进展的敏感性，可以用作疾病进展 临床试验的度量。