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

鞘脂和阿尔茨海默病发生和进展中的炎症

• 批准号: 8853439
• 负责人: Michelle M Mielke
• 金额: $ 31.72万
• 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/8853439
• 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; Diagnosis; 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; Pathology; Patients; Phenotype; Plasma; Process; Publishing; Research; Resources; Role; Sampling; Second Messenger Systems; Severities; Signal Pathway; Sphingolipids; Sphingomyelins; Spinal Puncture; Symptoms; TNF gene; TNFRSF5 gene; Testing; Tumor Necrosis Factor-alpha; Vascular Diseases; Visit; Work; aged; base; cell growth; clinical phenotype; cognitive change; fluorodeoxyglucose positron emission tomography; hippocampal atrophy; in vivo; inflammatory marker; innovation; mild cognitive impairment; population based; pre-clinical; prevent; public health relevance; research study; second messenger; 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）：与阿尔茨海默病[AD]相关的病理生理学脑变化在临床症状出现前开始数十年就开始了。虽然最近的进展已经导致了AD发病机制的临床前生物标志物模型（首先是淀粉样蛋白β [A β]病理，其次是神经变性，最后是认知症状），但这些病理变化的基础机制仍然未知，阻碍了潜在生物标志物和治疗靶点的鉴定。血液或CSF生物标志物的先前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，仅通过其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遗传缺陷的个体的混合物。 脑病理（例如，缺血病理学、神经变性、血管疾病）。本项目的首要目标是确定血浆和CSF鞘脂之间的时间关系（例如，神经酰胺、鞘磷脂）、ARF病理学（ARF成像、CSF ARF）和神经变性（FDG-PET低代谢、海马萎缩、CSF tau）的体内测量和临床终点。由于炎症与AD相关，并且与鞘脂密切相关，我们还将确定炎症过程（例如，TNF-α和IL-6）改变鞘脂和体内AD病理学之间的关联。虽然以前的研究已经检查了许多血浆和CSF生物标志物，但成功有限，但鞘脂的研究具有独特的前景和高度创新性。首先，细胞和动物研究表明鞘脂与AAF病理学和神经退行性变的测量之间存在直接联系。减少与神经酰胺水平相关的神经酰胺增加可预防神经退行性变。第二，我们始终证明，高水平的血浆鞘脂预测认知能力下降的个人谁是CN，MCI和AD。下一个合乎逻辑的步骤是确定鞘脂和AD病理学的体内证据之间的横截面和纵向关联。例如，我们将确定与具有异常Ablation和低神经酰胺的个体相比，具有异常Ablation和高神经酰胺的个体是否发展更多的神经变性和认知下降。为了实现我们的目标，我们将利用纵向收集的认知终点和在体内测量的阿尔茨海默病病理和神经退行性变的个体登记在人口为基础的马约诊所衰老研究[MCSA]和马约诊所阿尔茨海默病研究中心。这些纵向研究总共累积了超过2，375次对1，617名独特个体进行的AFDG成像，FDG-PET和MRI扫描，以及来自870名独特个体的超过1，085份CSF样本，为测试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CSF鞘脂之间的相互关系，AD病理学的发展和进展，以及临床症状的出现和进展。这项工作将有助于确定新的治疗策略，以延缓或可能预防AD。