Adiposity, Inflammation and Neurocognitive Decline in African Americans

描述(申请人提供)：阿尔茨海默病(AD)和痴呆症在美国大约有540万人受到影响，每68秒就有一个新病例被诊断出来。肥胖被认为是痴呆症和认知功能障碍的一个可修改的风险因素。肥胖和痴呆症对非裔美国人(AA)的影响不成比例，但在肥胖症和认知功能的研究中，AAs的代表性不足，而且肥胖症增加痴呆症风险的机制尚不清楚。此外，缺乏风险评分来帮助临床医生确定AA存在认知功能障碍的风险。我们将使用热那亚研究来研究肥胖可能影响大脑结构、认知功能(横断面)和认知衰退(纵向)的血管和非血管机制，热那亚研究是AA兄弟姐妹的队列。肥胖测量、传统和新型生物标记物以及血管危险因素将被用于开发一种针对再障的认知功能障碍临床风险工具。我们假设一系列肥胖效应通过炎症、脂肪因子和血管危险因子途径发生，这些途径对认知功能/衰退起有害作用。本研究的具体目的是：(1)量化横断面肥胖症与脑结构的关系，以及肥胖症与认知功能之间的横断面和纵向关系，说明大脑结构。我们假设：1.1)随着年龄的增长，中心性和全身性肥胖将与更多的脑萎缩、脑白质高信号、脑室增大和总脑体积减少相关。我们还假设，考虑到大脑结构、心血管危险因素和临床疾病：1.2)更大的肥胖将与较差的横断面认知功能相关；1.3)肥胖更大的增加将与更大的认知衰退相关；以及1.4)CT成像腹型肥胖的横断面关联与认知功能的关联将比腰围或体重指数更强。(2)比较脑结构、炎症、脂肪因子和血管疾病/危险因素在解释肥胖与认知功能/衰退关系中的中介作用。我们假设：炎症、脂肪因子和血管因素将比大脑结构更能解释肥胖与认知功能的横截面关联以及肥胖与认知衰退的关联。(3)开发临床风险评分来预测3.1)认知功能障碍和3.2)AA下降。我们假设，炎症生物标记物概况和肥胖措施将改善现有的心血管风险评分，以预测3.1)认知障碍和3.2)认知下降。拟议的分析将填补关于认知障碍的普遍和可改变的危险因素的知识的显著空白，并将提高临床医生识别认知功能障碍和针对性干预的高危AA的能力。

DESCRIPTION (provided by applicant): Alzheimer Disease (AD) and dementia affect an estimated 5.4 million people in the US with a new case diagnosed every 68 seconds. Obesity is a proposed modifiable risk factor for dementia and cognitive dysfunction. Obesity and dementia disproportionately affect African Americans (AA), yet AAs are underrepresented in studies of adiposity and cognitive function and mechanisms through which obesity increases dementia risk are poorly understood. In addition, risk scores to aid clinicians in identifying AA at risk of cognitive dysfunction are lacking. We will examine vascular and non-vascular mechanisms through which adiposity may affect brain structure, cognitive function (cross-sectional) and cognitive decline (longitudinal) using the GENOA study, a cohort of AA sibships. Adiposity measures, traditional and novel biomarkers, and vascular risk factors will be used to develop a cognitive dysfunction clinical risk tool for AA. We hypothesize a cascade of adiposity effects occurring through inflammation, adipokine, and vascular risk factor pathways which contribute deleteriously to cognitive function/decline. The specific aims of this study are: (1) Quantify cross-sectional adiposity and brain structure relationships, and cross-sectional and longitudinal relationships between adiposity and cognitive function, accounting for brain structure. We hypothesize that: 1.1) Greater central and overall adiposity will be associated with more brain atrophy, white matter hyperintensities, increased ventricular and decreased total brain volume across age. We also hypothesize that, accounting for brain structure, cardiovascular risk factors and clinical disease: 1.2) Greater adiposity will be associated with poorer cross-sectional cognitive function; and 1.3) Greater increases in adiposity will be associated with greater cognitive decline; and 1.4) Cross-sectional associations of CT-imaged abdominal adiposity will have stronger associations with cognitive function than waist circumference or body mass index. (2) Contrast the mediating effects of brain structure, inflammation, adipokines and vascular disease/risk factors in explaining relationships of adiposity to cognitive function/decline. We hypothesize that: Inflammation, adipokines and vascular contributors will explain 2.1) cross-sectional associations of adiposity to cognitive function and 2.2) associations of adiposity to cognitive decline, more so than brain structure. (3) Develop a clinical risk score to predict 3.1) cognitive dysfunction and 3.2) decline in AA. We hypothesize that an inflammation biomarker profile and adiposity measures will improve existing cardiovascular risk scores to predict 3.1) cognitive dysfunction and 3.2) cognitive decline. The proposed analyses will fill salient gaps in knowledge regarding prevalent and modifiable risk factors for cognitive impairment and will improve clinicians' ability to identify AA at high risk of cognitive dysfunction and decline for targeted interventions.