Adiposity, Inflammation and Neurocognitive Decline in African Americans

描述（由申请人提供）：阿尔茨海默病（AD）和痴呆症在美国影响着大约540万人，每68秒就有一个新病例被诊断出来。肥胖被认为是痴呆和认知功能障碍的可改变危险因素。肥胖和痴呆对非裔美国人的影响不成比例，但非裔美国人在肥胖和认知功能的研究中代表性不足，而且肥胖增加痴呆风险的机制尚不清楚。此外，尚无风险评分来帮助临床医生识别有认知功能障碍风险的AA。我们将研究血管和非血管机制，通过肥胖可能影响大脑结构，认知功能（横断面）和认知能力下降（纵向）使用GENOA研究，AA兄弟姐妹队列。肥胖测量、传统和新型生物标志物以及血管危险因素将被用于开发AA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/衰退有有害影响。本研究的具体目的是：(1)量化肥胖与脑结构的横断面关系，以及肥胖与认知功能的横断面和纵向关系，考虑脑结构。我们假设：1.1)随着年龄的增长，中枢性和全局性肥胖将与更多的脑萎缩、白质高信号、心室增大和脑总量减少相关。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)肥胖越大，横截面认知功能越差；1.3)肥胖增加越多，认知能力下降越严重；与腰围或体重指数相比，ct成像腹部肥胖的横断面相关性与认知功能的相关性更强。(2)对比脑结构、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、脂肪因子和血管因子将解释2.1)肥胖与认知功能的横断面关联，2.2)肥胖与认知能力下降的关联，而不是大脑结构。(3)制定临床风险评分，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志物和肥胖测量将改善现有的心血管风险评分，以预测3.1)认知功能障碍和3.2)认知能力下降。所提出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空白，并将提高临床医生识别认知功能障碍高风险AA和有针对性干预的能力。

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.