Sphingolipids and Inflammation in the Development and Progression of Alzheimer's

鞘脂与阿尔茨海默病发生和进展中的炎症

• 批准号: 9265377
• 负责人: Michelle M Mielke
• 金额: $ 37.88万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9265377
• 关键词: Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Animals; Apoptosis; Biological Markers; Blood; Brain; Brain Pathology; Cell membrane; Ceramides; Cerebrospinal Fluid; Clinic; Clinical; Cognition; Cognitive; Collection; Data; Dementia; Development; Disease; Enrollment; Goals; Image; Impaired cognition; Individual; Inflammation; Inflammatory; Interleukin-6; Link; Literature; Longitudinal Studies; MRI Scans; Magnetic Resonance Imaging; Measures; Memory Loss; Nerve Degeneration; Neurobehavioral Manifestations; Neurofibrillary Tangles; Outcome; Pathogenesis; Pathologic; Pathology; Patients; Phenotype; Plasma; Process; Publishing; Research; Resources; Role; Sampling; Second Messenger Systems; Severities; Signal Pathway; Sphingolipids; Sphingomyelins; Spinal Puncture; Symptoms; TNF gene; Testing; Vascular Diseases; Visit; Work; aged; base; biomarker development; cell growth; clinical Diagnosis; clinical phenotype; cognitive change; experimental study; fluorodeoxyglucose; fluorodeoxyglucose positron emission tomography; hippocampal atrophy; in vivo; inflammatory marker; innovation; mild cognitive impairment; population based; potential biomarker; pre-clinical; predictive marker; prevent; public health relevance; success; tau Proteins; tau phosphorylation; treatment strategy

 DESCRIPTION (provided by applicant): The pathophysiological brain changes associated with Alzheimer's disease [AD] begin decades before clinical symptoms. Although recent advances have led to a preclinical biomarker model of AD pathogenesis (first amyloid-beta [Aß] pathology, second neurodegeneration, and lastly cognitive symptoms), the mechanisms that underlie these pathological changes remain unknown, impeding the identification of potential biomarkers and treatment targets. Previous studies of blood or CSF biomarkers have mostly employed clinical outcomes (i.e., cognitively normal [CN], mild cognitive impairment [MCI] and AD. However, clinical phenotypes are heterogeneous. Thus, categorizing individuals by their clinical phenotype alone will include a mixture of individuals with varying types and severities of brain pathologies (e.g., Aß pathology, neurodegeneration, vascular disease). The overarching goal of this project is to determine the temporal relationship between plasma and CSF sphingolipids (e.g., ceramides, sphingomyelins), in vivo measures of Aß pathology (Aß imaging, CSF Aß) and neurodegeneration (FDG-PET hypometabolism, hippocampal atrophy, CSF tau), and clinical endpoints. As inflammation is associated with AD, and is intimately interrelated with sphingolipids, we will also determine whether inflammatory processes (e.g., TNF- and IL-6) modify the associations between sphingolipids and in vivo AD pathology. While previous studies have examined many plasma and CSF biomarkers with limited success, the study of sphingolipids is uniquely promising and highly innovative. First, cellular and animal studies demonstrate direct links between sphingolipids and measures of Aß pathology and neurodegeneration. Reducing Aß-associated increases in ceramide levels prevents neurodegeneration. Second, we consistently demonstrate that high levels of plasma sphingolipids predict cognitive decline among individuals who are CN, MCI, and AD. The next logical step is to determine the cross-sectional and longitudinal associations between the sphingolipids and in vivo evidence of AD pathology. For example, we will determine whether individuals with both abnormal Aß and elevated ceramides develop more neurodegeneration and cognitive decline compared to individuals with abnormal Aß and low ceramides. To accomplish our goals we will utilize a longitudinal collection of cognitive endpoints and in vivo measures of Aß pathology and neurodegeneration from individuals enrolled in the population-based Mayo Clinic Study of Aging [MCSA] and the Mayo Clinic Alzheimer's Disease Research Center. Together these longitudinal studies have accumulated over 2,375 visits with Aß imaging, FDG-PET, and MRI scans on 1,617 unique individuals, and more than 1,085 CSF samples from 870 unique individuals, providing an ideal resource to test our hypotheses. The proposed research will further our understanding of the interrelationship between plasma and CSF sphingolipids, the development and progression of AD pathology, and the emergence and progression of clinical symptoms. This work will contribute to the identification of new treatment strategies for delaying, or possibly preventing, AD.

 描述（由申请人提供）：与阿尔茨海默氏病 [AD] 相关的病理生理学大脑变化在临床症状出现之前几十年就开始了，尽管最近的进展已经导致 AD 发病机制的临床前生物标志物模型（第一个是淀粉样蛋白 -β [Aß] 病理学，第二个是神经变性，以及最后的认知症状），这些病理变化背后的机制仍然未知，阻碍了潜在生物标志物和治疗靶点的识别，以前对血液或脑脊液生物标志物的研究大多采用临床结果。 （即认知正常 [CN]、轻度认知障碍 [MCI] 和 AD。然而，临床表型是异质的。因此，仅根据临床表型对个体进行分类将包括具有不同类型和严重程度的个体的混合体 脑部病理（例如 Aß 病理、神经变性、血管疾病）和神经变性（FDG-PET 代谢减退、海马萎缩、脑脊液）。由于炎症与 AD 相关，并且与鞘脂密切相关，因此我们还将确定炎症过程（例如 TNF-α 和 IL-6）是否会改变鞘脂与体内 AD 病理学之间的关联。虽然之前的研究对许多血浆和脑脊液生物标志物进行了检查，但取得的成功有限，但鞘脂的研究具有独特的前景和高度创新性。首先，细胞和动物研究证明了直接联系。其次，我们证明血浆鞘脂水平持续升高可预测 CN、MCI 和 AD 患者的认知能力下降。目的是确定鞘脂与 AD 病理学体内证据之间的横向和纵向关联。例如，我们将确定个体是否同时患有 Aß 异常。与 Aß 异常和神经酰胺水平较低的个体相比，神经酰胺水平升高会导致更多的神经退行性疾病和认知能力下降。为了实现我们的目标，我们将利用基于人群的 Mayo 中登记的个体的认知终点和 Aß 病理学和神经退行性疾病的体内测量数据进行纵向收集。衰老临床研究 [MCSA] 和 Mayo Clinic 阿尔茨海默氏病研究中心通过 Aß 成像、FDG-PET 和 MRI 进行的这些纵向研究已累计超过 2,375 次就诊。对 1,617 名独特个体以及来自 870 名独特个体的超过 1,085 个脑脊液样本进行扫描，为检验我们的假设提供了理想的资源。拟议的研究将进一步了解血浆和脑脊液鞘脂之间的相互关系、AD 病理学的发展和进展，这项工作将有助于确定延迟或可能预防 AD 的新治疗策略。