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

 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（A β）单体聚集成纤维状斑块，并导致过度磷酸化的tau蛋白丝、神经元缠结、神经胶质增生、神经元损失和痴呆。然而，Ablastoma斑块不是AD所特有的，并且在其他神经退行性疾病以及认知正常的患者中观察到，特别是在老年人中。尽管许多研究支持PET上纤维状血小板增加是未来认知能力下降的风险因素，但认知正常受试者中血小板斑块形成的原因和临床意义尚未完全了解。脓毒症是一种严重的全身炎症性疾病，可导致短期和长期的神经认知功能障碍。急性败血症导致线粒体功能障碍和氧化损伤。脓毒症后的长期脑功能障碍知之甚少。我们已经表明，在实验性脓毒症（LPS）大鼠脑中细胞因子和可溶性动脉瘤单体的短暂增加，但在整个观察间隔（7-9天）动脉瘤神经炎斑块的进行性积累。初步RNAseq分析表明，LPS的转录物水平增加，可能影响神经炎性动脉瘤斑块的形成、稳定或清除减少。我们假设脓毒症和其他全身性炎症性疾病导致神经炎症，导致动脉瘤性神经炎斑块负担，并增加认知功能障碍的风险。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。这一目标的成功的内在原因是非侵入性成像工具的发展，以跟踪脓毒症的急性和慢性神经病理学表现。具体目标是：（1）确定在大鼠脓毒症模型中积累的动脉瘤性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。这将在空间和时间上与线粒体功能障碍和氧化损伤的证据进行比较;（2）基于我们的初步RNAseq数据来定义由介导ApoE斑块形成和神经元损伤的实验性脓毒症引起的分子事件;（3）在大鼠中进行纵向神经认知测试以鉴定由实验性脓毒症引起的认知异常，并将这些发现与涉及异常的区域中的神经病理学相关联;（4）进行有和没有积极免疫调节的纵向研究，以确定LPS诱导的ARF斑块形成，相关的神经病理学病变，线粒体功能障碍和相关的神经认知异常可以被减轻或逆转;（5）开发最好地识别由实验性脓毒症引起的急性和慢性脑病理的成像策略，并将这些成像发现的变化与药理学免疫调节相关联（AIM 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。

 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.