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（由申请人提供）：阿尔茨海默病 (AD) 的经典淀粉样蛋白级联假说指出，可溶性淀粉样蛋白 β (Aß) 单体聚集成纤维斑块，并导致 tau 蛋白丝过度磷酸化、神经原纤维缠结、神经胶质增生、神经元损失和痴呆。 Aß 斑块并非 AD 所特有，也可见于其他神经退行性疾病以及认知正常的患者尽管许多研究支持 PET 中纤维状 Aß 的增加是未来认知能力下降（一种严重的全身炎症性疾病）的危险因素，但认知正常受试者中 Aß 斑块形成​​的原因和临床意义尚不完全清楚。 ，导致短期和长期的神经认知功能障碍，脓毒症会导致线粒体功能障碍和氧化损伤，但我们对脓毒症后的长期脑功能障碍知之甚少。患有实验性脓毒症 (LPS) 的大鼠大脑中存在 Aß 单体，但在整个观察间隔（7-9 天）内 Aß 神经炎斑块逐渐积累，初步 RNAseq 分析表明 LPS 转录物水平增加，可能影响形成、稳定或清除率降低。我们发现脓毒症和其他全身炎症会导致神经炎症，加重 Aß 神经炎斑块负担并增加风险。我们建议阐明脓毒症引起的脑功能障碍的分子基础、神经认知特征和长期结果，这一目标的成功本质是开发非侵入性成像工具来跟踪脓毒症的急性和慢性神经病理表现。具体目标是： (1) 确定大鼠脓毒症模型中积累的 Aß 神经炎斑块是否最终消退，或者它们是否导致与 AD 中发生的相同的下游神经病理学后果。暂时，以证明线粒体功能障碍和氧化损伤；(2) 根据我们的初步 RNAseq 数据，定义实验性脓毒症引起的介导 Aß 斑块形成​​和神经损伤的分子事件；(3) 在大鼠中进行纵向神经认知测试，以识别认知能力。 (4) 在有或没有积极免疫调节的情况下进行纵向研究，以确定 LPS 诱导的 Aß 斑块形成​​是否相关；神经病理学病变、线粒体功能障碍和相关的神经认知异常可以通过药物缓解或逆转；（5）开发能够最好地识别实验性脓毒症引起的急性和慢性脑病理学的成像策略，并将这些成像结果的变化与药物免疫调节相关联（目的） 4). 这些将包括先进的 microPET 和 MRI 技术，这些成像测量将通过大脑本身的相关组织进行验证。