Domains of Inflammation and Risk of Dementia

描述（由申请人提供）：对阿尔茨海默病（AD）病因学缺乏了解限制了制定预防措施或检测这种破坏性疾病早期发展的能力。最近的理论表明，AD的发展和/或进展涉及血管以及神经退行性成分。新的焦点已经指向研究炎症生物标志物和AD之间的关联，以提供血管起源的证据。由于纵向数据的可用性有限，并且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，这些研究中的结果不一致。这项研究提出检查代表血管疾病不同领域的生物标志物，以增加对银杏记忆研究（GEMS）队列参与者在痴呆和AD发展中变化的理解。我们还将研究这些生物标志物的水平与认知变化以及MRI图像中的脑病理学之间的关联。储存的GEMS组的血液样品将用于测量代表不同领域的炎性疾病的生物标志物：IL-6（一般全身性炎症）、五聚蛋白3和血清淀粉样蛋白P（血管炎症）、派-1和脂联素（代谢功能）、晚期糖基化终产物受体-β 2（氧化应激）和内皮素-1（内皮功能）。GEMS研究是检查这些关系的理想选择，因为它是一项前瞻性多中心研究，研究对象为75岁或以上的成年人，在7年的随访中，每6个月评估一次认知能力下降和痴呆发作。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，共有523名痴呆患者和1046名非痴呆对照者。将在基线和随访期间最多两个额外时间点获取储存的血液以测定生物标志物。统计方法将包括考克斯比例风险回归、多元线性回归和混合模型回归，用于数据的纵向分析。在模型中纳入时间依赖性变量、血管疾病的风险因素和心血管发病率将有助于阐明涉及这些生物标志物的途径沿着进展为痴呆和AD。在GEMS中发现的大量事件病例为这些分析提供了足够的把握度，无论是总体分析还是性别和ApoE基因型等亚组分析。这些发现将提供新的知识，可用于开发有效的筛查工具，重点是预防和早期发现痴呆症和AD。

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.