Cerebromicrovascular disease in elderly with diabetes

描述（由申请人提供）：糖尿病（DM）是一种发病率和死亡率高、费用高的普遍疾病。我们的目标是确定2型糖尿病改变大脑微循环并导致老年人脑组织损伤和认知能力下降的前瞻性机制。主要假设是：1。高血糖是老年2型糖尿病患者微血管疾病、血流调节紊乱和脑组织损伤的常见机制。炎症有助于脑室周围白质的神经解剖学改变和MRI上的白质高信号。3. 额叶和颞叶皮质和皮质下萎缩表现为2型糖尿病老年人的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A1C水平与2型糖尿病老年人脑血流量、皮质和皮质下脑容量、认知和平衡的进行性下降有关。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，与年龄和高血压相匹配)在基线和两年随访后。在Aim 1中，我们将确定2型糖尿病对局部脑组织体积和灌注的影响，以及大脑自动调节的动态。在目的2中，我们确定炎症对白质完整性的影响。在Aim 3中，我们将纵向确定较高的血红蛋白A1C水平是否会增加脑血流失调、脑萎缩的进展，并使认知和平衡结果恶化。使用3特斯拉MRI连续动脉自旋标记（CASL）图像，使用T1和T2加权图像和灌注图上的分割方法，量化区域灰质、白质和脑脊液体积。白质完整性将通过流体衰减反转恢复（FLAIR）和扩散张量成像（DTI） MRI来确定。利用多普勒超声确定脑血管对CO2挑战和体位应激的调节动力学。我们计划使用统计结构方程建模技术来表征糖尿病可能导致老年人认知能力下降的机制，并量化代谢糖尿病紊乱、脑血流量和脑萎缩之间的相互作用。该研究将提供关于2型糖尿病脑灌注和功能结局的新数据和生物标志物，可用于启动将脑保护作为预防糖尿病并发症的新目标的努力。公共卫生相关性：糖尿病（DM）是一种发病率和死亡率高、费用高的普遍疾病，使中风和痴呆的风险增加一倍。糖尿病影响脑血流调节，导致老年糖尿病患者脑损伤，认知和平衡能力恶化。该研究将提供关于2型糖尿病脑灌注和功能结局的新数据和生物标志物，可用于启动将脑保护作为预防糖尿病并发症的新靶点的工作。

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.