Modifiable cardiovascular factors linking type 2 diabetes and Alzheimer's disease

摘要 我们的目标是更好地了解2型糖尿病（T2 D）和阿尔茨海默病（AD）之间的联系。 虽然文献支持它们的关联，但其潜在机制尚不清楚。一些 肥胖相关合并症导致T2 D患者脑血管异常;其中：受损 葡萄糖控制、低度全身性炎症、高血压、血脂异常和阻塞性睡眠呼吸暂停。 这些合并症提供了T2 D和痴呆之间可能的机制联系。重要的是，这组 合并症（这里称为“可改变的血管因素”）随着体重减轻而改善。除了有 事实上，T2 D与全因痴呆、T2 D个体和前驱AD个体的加倍有关， 共有一组CNS异常（此处称为“CNS损伤”）：记忆缺陷、海马 萎缩、AD易感区域的脑葡萄糖摄取减少和脑血流量减少。 中枢神经系统异常的这种重叠支持了所观察到的脑异常的潜在共同途径 在T2 D和前驱AD中。我们建议，大的重量损失，这导致这些改善 可改变的血管因素，将导致上述中枢神经系统（CNS）的恢复 与T2 D相关的疾病我们将进行一项纵向研究，比较100名肥胖者， 接受减肥手术的T2 D患者与40名同样患有T2 D的肥胖患者组成的同等组， 进行手术（并且可能不会减轻体重或改善可改变的血管因素）。预期的大 减肥手术后体重的变化提供了一个独特的机会来研究肥胖是如何因果关系 与中枢神经系统损伤有关。受试者，35-55岁，基线BMI为30-50 kg/m2，50%为女性，将 研究两次，术前即刻（基线）和术后一年， 非手术肥胖T2 D组。CNS从损伤或中风中恢复显示出很大的个体差异，因此我们 将决定性别、教育和健康如何调节与以下疾病相关的中枢神经系统损伤的恢复： T2 D是由大量体重减轻引起的。我们还将确定血糖控制和其他可改变的 血管因子及其在一年内的变化介导了体重减轻和恢复之间的关系， 在此期间中枢神经系统损伤。2型糖尿病和痴呆症都是严重的公共卫生问题。这 这项研究将提供证据证明针对可改变的血管危险因素的预防策略是合理的， 导致T2 D患者患痴呆症的风险增加。通过靶向可变血管 在年轻的时候，在潜在的不可逆的大脑退化之前，我们将展示这一点的重要性。 在年轻人中，当干预措施可能最有效时。我们将利用可靠和有效的 采取措施，以确保可重复性。这项研究有很强的科学前提，并得到了充分的 动力十足成功的保证是获得参与者，一个良好的环境，和经验， 调查人员的生产力。

ABSTRACT We aim to better understand the links between type 2 diabetes (T2D) and Alzheimer’s disease (AD). Although the literature supports their association, the underlying mechanisms are not known. A number of obesity-associated comorbidities contribute to cerebrovascular abnormalities in T2D; among them: impaired glucose control, low grade systemic inflammation, hypertension, dyslipidemia, and obstructive sleep apnea. These comorbidities provide possible mechanistic links between T2D and dementia. Importantly, this group of comorbidities (here referred to as “modifiable vascular factors”) improve with weight loss. In addition to the fact that T2D is related to a doubling of all-cause dementia, individuals with T2D and those with prodromal AD, share a cluster of CNS abnormalities (here referred to as “CNS impairments”): memory deficits, hippocampal atrophy, reductions in cerebral glucose uptake in AD-vulnerable regions, and decreased cerebral blood flow. This overlap in CNS abnormalities supports a potential common pathway for the brain abnormalities observed in T2D and prodromal AD. We propose that large weight loss, which results in improvements of these modifiable vascular factors, will lead to recovery of the above mentioned central nervous system (CNS) impairments associated with T2D. We will conduct a longitudinal study comparing 100 obese individuals with T2D undergoing bariatric surgery to an equivalent group of 40 obese individuals also with T2D who will not have surgery (and likely not lose weight or improve in the modifiable vascular factors). The anticipated large changes in weight after bariatric surgery present a unique opportunity to investigate how obesity is causally related to CNS impairments. Subjects, 35-55 years old, with baseline BMI of 30-50 kg/m2 and 50% female, will be studied twice, immediately pre-surgery (baseline) and one year post-surgery, and an equal interval for the non-surgical obese T2D group. CNS recovery from injury or stroke shows large individual variability, thus we will determine how sex, education, and fitness moderate CNS recovery of the impairments associated with T2D resulting from large weight loss. We will also ascertain whether glycemic control and other modifiable vascular factors and their change over one year mediate the relationships between weight loss and recovery of the CNS impairments during that period. Both T2D and dementia are significant public health problems. This study will provide evidence to justify prevention strategies targeting modifiable vascular risk factors that likely contribute to the increased risk of dementia among individuals with T2D. By targeting modifiable vascular factors at a young age, prior to potential irreversible brain deterioration, we will show the importance of this approach among young adults, when interventions may be most effective. We will utilize reliable and validated measures so as to ensure reproducibility. The study has a strong scientific premise and has been adequately powered. Success is assured by the access to participants, an excellent environment, and the experience and productivity of the investigators.