Causes, consequences, imaging and mitigation of sepsis-induced encephalopathy

脓毒症引起的脑病的原因、后果、影像学和缓解

• 批准号: 8916926
• 负责人: John M Hoffman
• 金额: $ 58.82万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8916926
• 关键词: Acute; Address; Adult; Affect; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Animals; Blood - brain barrier anatomy; Brain; Brain Pathology; Cerebral Edema; Cerebrum; Chronic; Cognitive; Contrast Media; Data; Dementia; Deposition; Development; Diffusion Magnetic Resonance Imaging; Disease; Early Diagnosis; Elderly; Encephalopathies; Escherichia coli; Event; Filament; Functional disorder; Future; Genes; Gliosis; Goals; Health; Hippocampus (Brain); Image; Imaging Device; Impaired cognition; Infection; Inflammation; Inflammation Mediators; Inflammatory; Injury; Lead; Learning; Lesion; Link; Lipopolysaccharides; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Mediating; Metabolic; Metabolism; Methods; Modeling; Molecular; Molecular Target; Neurocognitive; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurologic; Neurons; Organ; Outcome; Patients; Play; Positron-Emission Tomography; Protons; Rattus; Relative (related person); Risk; Risk Factors; Role; Senile Plaques; Sepsis; Serum; Spin Trapping; Tauopathies; Techniques; Time; Tissues; Transcript; Up-Regulation; abeta accumulation; age related; base; clinically significant; cognitive capacity; cytokine; fluorodeoxyglucose positron emission tomography; hyperphosphorylated tau; immunoregulation; juvenile animal; microPET; mitochondrial dysfunction; monomer; neurocognitive test; neuroinflammation; neuron loss; neuropathology; non-invasive imaging; novel; oxidative damage; public health relevance; response; success; tau Proteins; therapy development; transcriptome sequencing

 DESCRIPTION (provided by applicant): The classical amyloid cascade hypothesis of Alzheimer's disease (AD) states that soluble amyloid beta (Aß) monomers aggregate into fibrillar plaques and lead to hyperphosphorylated tau protein filaments, neurofibrillary tangles, gliosis, neuronal loss and dementia. However, Aß plaques are not specific to AD, and are seen with other neurodegenerative disorders as well as cognitively normal patients, particularly in the elderly. The causes and clinical significance of Aß plaque formation in cognitively normal subjects is not fully understood although numerous studies support that increased fibrillar Aß on PET is a risk factor for future cognitive decline. Sepsis, a severe systemic inflammatory condition, results in short and long term neurocognitive dysfunction. Acutely, sepsis causes mitochondrial dysfunction and oxidative damage. Longer-term brain dysfunction following sepsis is poorly understood. We have shown a transient increase in cytokines and soluble Aß monomers in the rat brain with experimental sepsis (LPS) but progressive accumulation of Aß neuritic plaques throughout the interval of observation (7-9 d). Preliminary RNAseq analysis suggests increased levels of transcripts with LPS that may affect formation, stabilization or reduced clearance of neuritic Aß plaques. We hypothesize that sepsis and other systemic inflammatory conditions result in neuroinflammation, contribute to Aß neuritic plaque burden and increase the risk of cognitive dysfunction. We proposed to clarify the molecular basis, neurocognitive features, and long-term outcome of sepsis-induced brain dysfunction. Inherent in the success of this goal is the development of non-invasive imaging tools to track acute and chronic neuropathological manifestations of sepsis. The specific aims are: (1) To determine whether Aß neuritic plaques that accumulate in the rat sepsis model eventually resolve or whether they result in the same downstream neuropathological consequences as occur in AD. This will be compared, spatially and temporally, to evidence for mitochondrial dysfunction and oxidative damage; (2) to define molecular events resulting from experimental sepsis that mediate Aß plaque formation and neuronal damage based on our preliminary RNAseq data; (3) To perform longitudinal neurocognitive tests in rats to identify cognitive abnormalities resulting from experimental sepsis, and correlate these findings with neuropathology in regions implicated as abnormal; (4) To perform longitudinal studies with and without aggressive immune modulation to determine whether LPS-induced Aß plaque formation, associated neuropathological lesions, mitochondrial dysfunction and associated neurocognitive abnormalities can be pharmacologically mitigated or reversed; (5) to develop imaging strategies that best identify both acute and chronic brain pathology resulting from experimental sepsis, and correlate changes in these imaging findings with pharmacologic immune modulation (aim 4). These will include advanced microPET and MRI techniques. These imaging measures will be validated by relevant tissue correlates in the brain itself.

 描述（由适用提供）：阿尔茨海默氏病（AD）的经典淀粉样蛋白级联假设指出，固体淀粉样蛋白β（Aß）单体聚集成纤维状斑块，并导致热磷酸化的TAU tau蛋白质蛋白丝，神经纤维纤维蛋白质，胶状缠结，胶状，神经元，神经元和层。但是，Aß斑块并非特定于AD，并且与其他神经退行性疾病以及认知正常的患者（尤其是最古老的患者）一起可见。尽管许多研究支持增加了Fibrillaraß对PET，但尚未完全了解Aß斑块形成在认知正常受试者中的原因和临床意义，这是未来认知能力下降的危险因素。败血症是一种严重的全身性炎症状况，导致短期和长期神经认知功能障碍。急性，败血症会导致线粒体功能障碍和氧化损伤。败血症后的长期脑功能障碍知之甚少。在观察过程中，我们已经显示了大鼠脑中细胞因子和固体Aß单体的瞬时增加，但在观察到的整个观察区间（7-9 d）中逐渐增加了Aß神经质斑块的逐步积累。初步RNASEQ分析表明，通过LPS的转录本水平增加，可能会影响神经质Aß斑块的形成，稳定或降低清除率。我们假设败血症和其他全身性炎症状况会导致神经炎症，导致Aß神经质斑块燃烧并增加认知功能障碍的风险。我们建议阐明败血症诱导的脑功能障碍的分子基础，神经认知特征和长期结局。该目标成功固有的是开发非侵入性成像工具，以跟踪败血症的急性和慢性神经病理学表现。具体目的是：（1）确定在大鼠败血症模型中积累的Aß神经质斑块最终会解决，还是导致与AD中发生的下游神经病理学后果。这将在空间和临时上与线粒体功能障碍和氧化损伤进行比较。 （2）根据我们的初步RNASEQ数据介导Aß斑块形成和神经元损伤的实验性败血症产生的分子事件； （3）在大鼠中进行纵向神经认知测试，以鉴定实验性败血症导致的认知异常，并将这些发现与实现为异常的区域中的神经病理相关。 （4）进行有或没有侵袭性免疫调节的纵向研究，以确定LPS诱导的Aß斑块形成，相关的神经病变病变，线粒体功能障碍以及相关的神经认知异常是否可以在药理学上受到药物治疗或相关的抑制作用； （5）制定最能确定实验性败血症导致的急性和慢性脑病理学的成像策略，并将这些成像发现中的变化与药物免疫调节相关联（AIM 4）。这些将包括高级微型网络和MRI技术。这些成像措施将通过大脑本身的相关组织相关。