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: 9514782
• 负责人: Michelle M Mielke
• 金额: $ 38.08万
• 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 2020-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9514782
• 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; Positron-Emission Tomography; Process; Publishing; Research; Resources; Role; Sampling; Second Messenger Systems; Senile Plaques; 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.



项目成果

Sphingolipids as prognostic biomarkers of neurodegeneration, neuroinflammation, and psychiatric diseases and their emerging role in lipidomic investigation methods.

• DOI: 10.1016/j.addr.2020.04.009
• 发表时间: 2020
• 期刊: Advanced drug delivery reviews
• 影响因子: 16.1
• 作者: van Kruining D;Luo Q;van Echten-Deckert G;Mielke MM;Bowman A;Ellis S;Oliveira TG;Martinez-Martinez P
• 通讯作者: Martinez-Martinez P

Burden and management of type 2 diabetes in rural United States.

• DOI: 10.1002/dmrr.3410
• 发表时间: 2021-07
• 期刊: Diabetes/metabolism research and reviews
• 作者: Dugani SB;Mielke MM;Vella A
• 通讯作者: Vella A