Domains of Inflammation and Risk of Dementia

描述（由申请人提供）：缺乏对阿尔茨海默病（AD）病因的了解限制了制定预防措施或发现这种破坏性疾病早期发展的能力。最近的理论表明，AD的发生和/或进展涉及血管和神经退行性成分。新的研究重点是研究炎症生物标志物与AD之间的关系，以提供血管起源的证据。由于纵向数据的可用性有限，以及缺乏对可能反映炎症不同方面的不同炎症标志物的同时测量，这些研究的结果不一致。本研究提出检测代表不同血管疾病领域的生物标志物，以增加对它们在银杏记忆评估研究（GEMS）队列参与者中痴呆和AD发展中的变化的理解。我们还将在MRI图像中研究这些生物标志物水平与认知变化以及脑病理之间的关系。GEMS队列中储存的血液样本将用于测量代表不同领域的炎症疾病的生物标志物：IL-6（全身性炎症）、戊烷素3和血清淀粉样蛋白P（血管炎症）、PAI-1和脂联素（代谢功能）、晚期糖基化终产物受体- RAGE（氧化应激）和内皮素-1（内皮功能）。GEMS研究是检验这些关系的理想方法，因为它是一项前瞻性多地点研究，研究对象是75岁或以上的成年人，每6个月对他们进行一次认知能力下降和痴呆发作的评估，随访7年。使用MRI图像和标准化标准确定痴呆亚型，即AD和血管性痴呆。临床试验结果显示，银杏叶和安慰剂在痴呆、AD、MCI、死亡率和CVD终点的主要结局方面没有差异。这项GEMS的辅助研究是一项病例队列设计，包括523名痴呆患者和1046名非痴呆对照组。储存的血液将在基线和随访期间最多两个额外的时间点用于测定生物标志物。统计方法将包括Cox比例风险回归、多元线性回归和混合模型回归的纵向分析数据。在模型中纳入时间相关变量、血管疾病的危险因素和心血管发病率将有助于阐明这些生物标志物在痴呆和AD进展过程中的途径。在GEMS中发现的大量事件病例为这些总体和亚组（如性别和ApoE基因型）内的分析提供了足够的力量。这些发现将提供新的知识，可用于开发有效的筛查工具，重点关注痴呆症和阿尔茨海默病的预防和早期发现。

DESCRIPTION (provided by applicant): The lack of understanding of Alzheimer's disease (AD) etiology limits the ability to develop preventive measures or to detect early development of this destructive disease. Recent theory suggests that the development and/or progression of AD involves vascular as well as neurodegenerative components. New focus has been directed toward investigating the associations between inflammatory biomarkers and AD to provide evidence of the vascular origin. The findings in these studies are inconsistent due to the limited availability of longitudinal data and lack of simultaneous measurement of different inflammatory markers which may reflect different aspects of inflammation. This study proposes to examine biomarkers representing different domains of vascular disease to increase understanding of how they vary in the development of dementia and AD among participants of the Ginkgo Evaluation of Memory Study (GEMS) cohort. We will also investigate the association between levels of these biomarkers and changes in cognition as well as brain pathology in MRI images. Stored blood samples of the GEMS cohort will be used to measure biomarkers of inflammatory disease representing different domains: IL-6 (general systemic inflammation), pentraxin 3 and serum amyloid P (vascular inflammation), PAI-1 and adiponectin (metabolic function), receptor for advanced glycation endproduct - RAGE (oxidative stress) and endothelin-1 (endothelial function). The GEMS Study is ideal for examining these relationships as it is a prospective multi-site study of adults age 75 or older who were evaluated every six month for cognitive decline and dementia onset over 7 years of follow-up. Subtype of dementia, i.e. AD and vascular dementia, were determined using MRI images and standardized criteria. The clinical trial resulted in no differences between Ginkgo biloba and placebo for primary outcomes of dementia, AD, MCI, mortality and CVD endpoints. This ancillary study to GEMS is a case-cohort design of 523 participants with incident dementia and 1046 non-demented controls. Stored blood will be accessed to assay biomarkers at baseline and for up to two additional time points during follow-up. Statistical approaches will include Cox proportional hazards regression, multiple linear regression, and mixed models regression for longitudinal analysis of data. Inclusion of time-dependent variables, risk factors for vascular disease, and cardiovascular morbidities in models will help elucidate pathways involving these biomarkers along the progression to dementia and AD. The large number of incident cases that were found in GEMS provides adequate power for these analyses overall and within subgroups such as gender and ApoE genotype. These findings will provide new knowledge that can be used to develop effective screening tools to focus on prevention as well as early detection of dementia and AD.