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

 描述(由申请人提供)：与阿尔茨海默病[AD]相关的病理生理脑变化在临床症状出现前几十年就开始了。尽管最近的进展导致了AD发病机制的临床前生物标志物模型(第一次淀粉样β[Aü]病理，第二次神经变性，最后是认知症状)，但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，临床表型是不同的。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混合个体 脑部病理(例如，A？病理、神经变性、血管疾病)。该项目的总体目标是确定血浆和脑脊液鞘磷脂(例如神经酰胺、鞘磷脂)、体内A？病理(A？成像、脑脊液？)和神经变性(FDG-PET代谢不足、海马萎缩、脑脊液tau)和临床终点之间的时间关系。由于炎症与AD相关，并与鞘脂密切相关，我们还将确定炎症过程(例如，肿瘤坏死因子-和IL-6)是否会改变鞘脂与体内AD病理之间的联系。虽然之前的研究检测了许多血浆和脑脊液生物标志物，但成功有限，但鞘脂的研究具有独特的前景和高度的创新性。首先，细胞和动物研究证明神经鞘脂脂与A？病理和神经退行性变之间存在直接联系。减少神经酰胺水平的增加可防止神经退行性变。其次，我们一直证明，高水平的血浆鞘脂可以预测CN、MCI和AD患者的认知能力下降。下一个合乎逻辑的步骤是确定鞘脂和AD病理活体证据之间的横截面和纵向关联。例如，我们将确定与Aü异常和神经酰胺低的个体相比，Aü异常和神经酰胺升高的个体是否会出现更多的神经退行性变和认知能力下降。为了实现我们的目标，我们将利用认知终点的纵向收集，以及来自基于人群的梅奥老年诊所研究[MCSA]和梅奥诊所阿尔茨海默病研究中心登记的个体的A？病理和神经变性的活体测量。这些纵向研究累积了超过2,375次访问，对1,617个独特的个体进行了A？成像、FDG-PET和MRI扫描，以及来自870个独特个体的1,085个脑脊液样本，为检验我们的假设提供了理想的资源。这项研究将进一步加深我们对血浆和脑脊液鞘脂之间的相互关系，AD病理的发展和进展，以及临床症状的出现和进展的理解。这项工作将有助于确定延缓或可能预防AD的新治疗策略。

 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.