Domains of Inflammation and Risk of Dementia

描述(申请人提供)：缺乏对阿尔茨海默病(AD)病因学的了解，限制了制定预防措施或检测这种破坏性疾病的早期发展的能力。最近的理论认为，AD的发生和/或进展涉及血管和神经退行性成分。研究炎性生物标记物与阿尔茨海默病之间的关系，以提供血管起源的证据已成为新的焦点。这些研究的结果是不一致的，因为纵向数据有限，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。这项研究建议检查代表血管疾病不同领域的生物标记物，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阿尔茨海默病发展过程中的变化的理解。我们还将在MRI图像中调查这些生物标记物的水平与认知变化和脑病理之间的关系。GEMS队列的储存血液样本将用于测量代表不同领域的炎症性疾病的生物标记物：IL-6(全身炎症)、五角蛋白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选择，因为它是一项前瞻性的多地点研究，对象是75岁或以上的成年人，他们在7年的随访中每6个月接受一次认知能力下降和痴呆症发病的评估。用MRI图像和标准化标准确定痴呆的亚型，即AD和血管性痴呆。临床试验结果表明，银杏叶制剂和安慰剂在痴呆症、AD、MCI、死亡率和心血管疾病终点方面的主要结果没有差异。这项对GEMS的辅助研究是一项病例队列设计，包括523名偶发痴呆症参与者和1046名非痴呆对照。储存的血液将在基线时进行生物标志物检测，并在后续最多两个额外的时间点进行检测。统计方法将包括COX比例风险回归、多元线性回归和用于数据纵向分析的混合模型回归。在模型中纳入时间依赖变量、血管疾病风险因素和心血管疾病发病率将有助于阐明这些生物标记物在痴呆和AD进展过程中的途径。在GEMS中发现的大量事件病例为这些分析提供了足够的能力，无论是在总体上还是在诸如性别和载脂蛋白E基因的亚组内。这些发现将提供新的知识，可用于开发有效的筛查工具，专注于痴呆症和阿尔茨海默病的预防和早期检测。 公共卫生相关性：该项目建议使用纵向测量的生物标记物来评估炎症和痴呆症、阿尔茨海默病和轻度认知障碍(MCI)不同领域之间的关联，该生物标记物对1569名银杏记忆评估队列的参与者进行了纵向测量。在认知症状出现之前评估这些生物标志物以预测痴呆症的风险，将提高制定预防和早期发现策略的能力。

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. PUBLIC HEALTH RELEVANCE: This project proposes to evaluate associations between different domains of inflammation and dementia, Alzheimer's disease, and mild cognitive impairment (MCI) using biomarkers measured longitudinally in 1569 participants of the Ginkgo Evaluation of Memory cohort. Assessment of these biomarkers to predict risk of dementia prior to cognitive symptoms emerging will increase ability to develop strategies of prevention and early detection.