Genetic and imaging analysis of cerebrovascular disease and cognition in diabetes

描述(申请人提供)：根据世界卫生组织的说法，有一种全球性的“糖尿病流行”。仅在美国，2007年糖尿病造成的损失估计为1,740亿美元。这笔费用的很大一部分是由于2型糖尿病伴随而来的许多问题，包括血管疾病和认知障碍风险的增加，这可能会限制日常生活能力和患者遵守治疗的能力。然而，关于遗传、环境和糖尿病相关因素(如血管疾病)对糖尿病人群中1200名受试者的心血管、遗传、流行病学和最先进的脑成像方法的相对贡献，我们知之甚少。该提案有三个具体目标，将申请者的神经科学背景与导师丰富的流行病学和遗传学经验结合起来：1)使用功能磁共振找出在工作记忆任务中与T2 DM有关的大脑区域；2) 评估预先定义的感兴趣区域内的MRI测量与 测量认知、脑血管健康、身体特征和大量先前获得的心血管疾病测量；3)进行遗传性和单核苷酸多态(SNP)关联分析。受试者将从之前的糖尿病和心血管疾病研究中招募，在那里获得了广泛的遗传和心血管测量，并将完成认知测试、临床测试(例如空腹血糖)和磁共振成像扫描，这些扫描将允许评估白质完整性、脑血流、脑容量和神经活动。将对fMRI数据进行体素全脑分析；将使用通用估计方程来建模MR数据、心血管和临床测量、身体特征和认知之间的流行病学关系；并将考虑流行病学分析中确定的特征的影响来估计功能性MRI测量的遗传度。从先前的DNA分析中获得的广泛的遗传数据库将被用来评估MRI特征的单核苷酸多态关联。在全球和美国，糖尿病已经达到了流行的程度。这项研究旨在整合最先进的认知、成像和遗传学技术，以更多地了解为什么2型糖尿病会增加认知障碍的风险。这些信息对确定糖尿病相关认知功能下降的生物学原因、设计有效的治疗方法和提供预防策略非常重要。

DESCRIPTION (provided by applicant): According to the WHO there is a global "diabetes epidemic." In the United States alone, the cost of diabetes in 2007 was estimated at $174 billion. Much of this expense is due to the many problems that accompany type 2 diabetes, including vascular disease and increased risk for cognitive impairments, which may limit activities of daily living and the patients' ability to comply with treatments. However, little is known about the relative contributions of genetics, environment, and diabetes-associated factors such as vascular disease to cardiovascular, genetic, epidemiological, and state of the art brain imaging methods for 1200 subjects in a diabetes-enriched population. The proposal has three specific aims that combine the applicant's neuroscience background with the mentor's extensive epidemiological and genetic experience: 1) Identify brain regions that exhibit an association with T2DM during a working memory task using functional MRI; 2) Assess epidemiological relationships between MRI measures within pre-defined regions of interest and measures of cognition, cerebrovascular health, physical characteristics, and extensive previously acquired measures of cardiovascular disease; 3) Perform heritability and single nucleotide polymorphism (SNP) association analyses. Subjects will be recruited from a previous study of diabetes and cardiovascular disease where extensive genetic and cardiovascular measures were acquired and will complete a cognitive test battery, clinical tests (e.g., fasting blood glucose), and MR imaging scans that will allow assessment of white matter integrity, cerebral perfusion, brain volume, and neural activity. Voxel-wise whole brain analyses will be performed on the fMRI data; generalized estimating equations will be used to model epidemiological relationships between MR-derived data, cardiovascular and clinical measures, physical characteristics, and cognition; and the heritability of functional MRI measures will be estimated taking into account the influence of characteristics identified in the epidemiological analysis. The extensive genetic database derived from prior DNA analysis will be used to assess single nucleotide polymorphism association of MRI traits. Globally and in the US, diabetes has reached epidemic proportions. This study aims to integrate state of the art cognitive, imaging, and genetics techniques to learn more about why type 2 diabetes increases the risk for cognitive impairments. This information is important to establish the biological causes for diabetesrelated cognitive decline, design effective treatments and inform preventative strategies.