Cerebromicrovascular disease in elderly with diabetes

描述（由申请人提供）：糖尿病（DM）是一种普遍的、昂贵的疾病，具有高发病率和死亡率。我们的目标是前瞻性地确定2型糖尿病改变脑微循环并导致老年人脑组织损伤和认知能力下降的机制。主要假设是：1.高血压是老年2型糖尿病患者微血管疾病、血流调节障碍和脑组织损伤的常见机制。2.炎症导致脑室周围白色物质和MRI上白色物质高信号的神经解剖学改变。3.在2型糖尿病老年人中，额叶和颞叶区域的皮质和皮质下萎缩表现为执行功能障碍和平衡障碍。糖尿病严重程度和较高的血红蛋白A1 C水平与2型糖尿病老年人的脑血流量、皮质和皮质下脑容量以及认知和平衡的进行性下降相关。我们将前瞻性研究60名糖尿病患者和60名对照受试者（50-85岁，年龄和高血压相匹配）的基线和两年随访。在目的1中，我们将确定2型糖尿病对局部脑组织体积和灌注，脑自动调节动力学的影响。在目标2中，我们确定炎症对白色物质完整性的影响。在目标3中，我们将纵向确定较高的血红蛋白A1 C水平是否会增加脑血流失调、脑萎缩的进展以及认知和平衡结果的恶化。将使用在T1和T2加权图像和灌注图上应用的分割方法，在3 T MRI下使用连续动脉自旋标记（CASL）图像，对区域灰质、白色物质和脑脊液体积进行定量。将通过液体衰减反转恢复（FLAIR）和扩散张量成像（DTI）MRI确定白色物质完整性。将使用多普勒超声确定脑血管调节对CO2激发和直立性应激的动力学。我们计划使用统计结构方程模型技术来表征糖尿病可能导致老年人认知能力下降的机制，并量化糖尿病代谢紊乱、脑血流和脑萎缩之间的相互作用。这项研究将提供有关2型糖尿病脑灌注和功能结局的新数据和生物标志物，可用于启动实施脑保护作为糖尿病并发症新靶点预防的努力。公共卫生相关性：糖尿病（DM）是一种流行的、昂贵的疾病，具有高发病率和死亡率，使中风和痴呆的风险增加一倍。糖尿病影响大脑的血流调节，导致老年糖尿病患者的脑损伤和认知和平衡恶化。这项研究将提供有关2型糖尿病脑灌注和功能结局的新数据和生物标志物，可用于启动实施脑保护作为预防糖尿病并发症的新靶点的努力。

DESCRIPTION (provided by applicant): Diabetes mellitus (DM) is a prevalent, costly condition with high morbidity and mortality. Our goal is to determine prospectively mechanisms by which type 2 DM alters cerebral microcirculation and contributes to brain tissue damage and cognitive decline in the elderly. The primary hypotheses are: 1. Hyperglycemia is a common mechanism for microvascular disease, disturbance in blood flow regulation and brain tissue damage in older adults with type 2 DM. 2. Inflammation contributes to neuroanatomical changes in periventricular white matter and white matter hyperintensities on MRI. 3. Cortical and subcortical atrophy in frontal and temporal regions manifests as executive dysfunction and impairment of balance in older adults with type 2 DM. Diabetes severity and higher hemoglobin A1C levels are associated with progressive decline in cerebral blood flow, cortical and subcortical brain volumes, and cognition and balance in older adults with type 2 DM. We will prospectively study 60 diabetic and 60 control subjects (50-85 years old, matched by age and hypertension) at baseline and after a two-year follow-up. In the Aim 1 we will determine the effects of type 2 DM on regional brain tissue volumes and perfusion, dynamics of cerebral autoregulation. In Aim 2 we determine the effects of inflammation on white matter integrity. In the Aim 3 we will determine longitudinally if higher hemoglobin A1C levels increase progression of cerebral blood flow dysregulation, brain atrophy and worsen cognitive and balance outcomes. Regional gray, white matter and cerebrospinal fluid volumes will be quantified using a segmentation method applied on T1- and T2- weighted images and perfusion maps, using a continuous arterial spin labeling (CASL) images at 3 Tesla MRI. White matter integrity will be determined from fluid attenuated inversion recovery (FLAIR) and diffusion tensor imaging (DTI) MRI. Dynamics of cerebral vasoregulation to CO2 challenge and orthostatic stress will be determined using Doppler ultrasound. We plan to use statistical structural equation modeling technique to characterize the mechanisms by which diabetes may lead to cognitive decline in older people, and to quantify interactions among metabolic diabetic disturbance, cerebral blood flow and brain atrophy. This study will provide new data and biomarkers on cerebral perfusion and functional outcomes in type 2 DM that can be used to initialize the efforts to implement brain protection as a new target prevention of DM complications. PUBLIC HEALTH RELEVANCE: Diabetes mellitus (DM) is a prevalent, costly condition with high morbidity and mortality that doubles the risk for stroke and dementia. DM affects blood flow regulation in the brain, that leads to brain damage and worsening of cognition and balance in older diabetic adults. This study will provide new data and biomarkers on cerebral perfusion and functional outcomes in type 2 DM, that can be used to initialize the efforts to implement brain protection as a new target for prevention of DM complications.