Obesity and Type-2 Diabetes: Bariatric Surgery Effects on Brain Function

描述(申请人提供)：这项拟议的研究将描述慢性肥胖对大脑功能影响的潜在机制，并确定减肥手术和减肥的认知益处是否有助于使用多模式神经成像方法评估增强的大脑代谢或血流动力学功能。手术后改善糖尿病相关的胰岛素-血糖紊乱的作用将被测试。肥胖症已经达到了流行的程度，现在是一个主要的公共卫生问题，导致了包括大脑障碍在内的各种共病疾病。越来越多的证据表明，即使在没有糖尿病、心血管疾病和中风等并存疾病的情况下，慢性肥胖也可能对大脑产生不利影响。我们之前已经证明，身体质量指数(BMI)升高与认知功能下降有关。减肥手术越来越多地被用作治疗慢性病态肥胖症。除了使许多患者的体重大幅下降外，减肥手术还改变了全身代谢和血管功能，包括改变胰岛素和葡萄糖代谢。我们在一项多中心纵向研究中的初步发现 减肥手术的研究表明，在手术后12周，人们的神经认知功能，包括记忆回忆，都会得到改善。这些益处持续超过12个月，不仅与体重减轻有关，还与潜在风险因素的变化有关，例如代谢功能的改善和2型糖尿病的缓解。神经成像提供了一种潜在的强大的生物标记物，可以反映大脑结构和功能(例如，功能磁共振成像)以及大脑病理生理的变化。到目前为止，还没有发表的研究按照这项研究的建议检查减肥手术后神经元、代谢和血管脑部的变化。我们的初步神经成像数据显示，功能磁共振成像显示脑功能反应增强，动脉自旋标记(ASL)显示局部脑血流量增加，磁共振波谱(MRS)显示大脑代谢物水平改变。我们假设：1)与肥胖相关的大脑代谢和血流动力学障碍对大脑功能产生不利影响(从认知测试和功能磁共振成像中可以明显看出)；2)减肥手术后体重减轻和相关的代谢变化改善了大脑功能；以及3)神经认知和神经功能(FMRI)的增强是由于大脑代谢(MRS)和血管(ASL)功能的改善。糖尿病的缓解预计是造成这些影响的一个因素，尽管这种影响也将与改善脑部(MRS)和全身(如血清细胞因子)代谢健康和脑血流(ASL)有关。前瞻性纵向队列配对设计将用于评估这些神经影像指标在手术前后和相对非手术肥胖对照中的变化。糖尿病患者和非糖尿病肥胖患者的比例相等，这使我们能够测试其影响。通过在减肥手术的背景下研究肥胖和减肥，这项研究利用了一种强大的自然实验操作，可以为了解肥胖和减肥对大脑的影响提供一个独特的窗口。

DESCRIPTION (provided by applicant): The proposed study will delineate mechanism underlying the effects of chronic obesity on brain functioning and determine if cognitive benefits of bariatric surgery and weight loss contribute to enhanced cerebral metabolic or hemodynamic function assessed using multimodal neuroimaging methods. The contribution of post-surgical improvements in diabetes-associated insulin-glucose disturbances will be tested. Obesity has reached epidemic proportions and is now a major public health problem, contributing to various comorbid medical conditions, including brain disturbances. There is increasing evidence that chronic obesity may adversely affect the brain, even in the absence of comorbid diseases, such as diabetes, cardiovascular disease, and stroke. We have previously shown that elevated body mass index (BMI) is associated with reduced cognitive function. Increasingly, bariatric surgery is being used as a treatment for chronic morbid obesity. Besides causing dramatic weight loss in many patients, bariatric surgery alters systemic metabolic and vascular function, including altering insulin and glucose metabolism. Our initial findings from a multicenter longitudinal study of bariatric surgery indicated that people experience improvements in neurocognitive functioning, including memory recall, by 12 weeks post-surgery. These benefits continue over 12 months and are related not only to the amount of weight lost, but also changes in underlying risk factors, such as improved metabolic function, and remission of type-2 diabetes Neuroimaging provides a potentially powerful biomarker of alterations in brain structure and function (e.g., FMRI), as well as cerebral pathophysiology. To date no published studies have examined neuronal, metabolic and vascular brain changes following bariatric surgery as proposed in this study. Our preliminary neuroimaging data indicates enhanced functional brain response on FMRI, increased regional cerebral blood flow on arterial spin labeling (ASL), and changes in cerebral metabolite levels on magnetic resonance spectroscopy (MRS). We hypothesize that: 1) Cerebral metabolic and hemodynamic disturbances linked to obesity adversely affect brain function (evident from cognitive testing and FMRI); 2) Weight loss and associated metabolic changes post-bariatric surgery improve brain functions; and 3) Enhanced neurocognitive and neuronal function (FMRI) are due to improved cerebral metabolic (MRS) and vascular (ASL) function. Remission of diabetes is expected to be one factor accounting for these effects, though this effect will also be tied to improved cerebral (MRS) and systemic (e.g., serum cytokines) metabolic health and cerebral perfusion (ASL). A prospective longitudinal cohort matched design will be used to assess changes in these neuroimaging indices, pre- and post-surgery and relative non-surgical obese controls. The groups will have equal proportions of diabetics and non-diabetics with obesity, enabling us to test its influence. By examining obesity and weight loss in the context of bariatric surgery, this study capitalizes on a powerful natural experimental manipulation that can provide a unique window into the effects of obesity and weight loss on the brain.