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(T2D)和阿尔茨海默病(AD)之间的联系。 尽管文献支持它们之间的联系，但其潜在的机制尚不清楚。一批 肥胖相关的合并症导致T2D患者的脑血管异常；其中包括：受损 血糖控制、低度全身炎症、高血压、血脂异常和阻塞性睡眠呼吸暂停。 这些并存提供了T2D和痴呆症之间可能的机械联系。重要的是，这群人 合并症(这里指的是“可改变的血管因素”)会随着体重减轻而改善。除 事实是，T2D与全因痴呆症、T2D患者和前驱AD患者的发病率翻了一番， 共享一组中枢神经系统异常(在此称为“中枢神经系统损伤”)：记忆缺陷、海马区 萎缩，AD易感区域大脑葡萄糖摄取减少，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 T2D和先兆AD。我们建议大幅减肥，从而改善这些 可改变的血管因子，将导致上述中枢神经系统(CNS)的恢复 与T2D相关的损害。我们将进行一项纵向研究，将100名肥胖者与 接受T2D减肥手术的40名同样患有T2D的肥胖者 做手术(而且很可能不会减轻体重或改善可改变的血管因子)。预期中的大型 减肥手术后体重的变化为研究肥胖的原因提供了一个独特的机会 与中枢神经系统损伤有关。受试者，年龄35-55岁，基线BMI为30-50公斤/平方米，50%为女性，将 进行两次研究，即刻术前(基线)和术后一年，并在相同的时间间隔 非手术肥胖T2D组。从损伤或中风中恢复的中枢神经系统显示出很大的个体差异性，因此我们 将决定性别、教育程度和健康状况如何调节中枢神经系统相关损害的恢复 由于体重大幅下降而导致的T2D。我们还将确定血糖控制和其他可修改的 血管因素及其一年变化在减肥与康复关系中的中介作用 在此期间，中枢神经系统受损。T2D和痴呆症都是重大的公共卫生问题。这 研究将提供证据来证明针对可改变的血管风险因素的预防策略的合理性 导致患有T2D的个体患痴呆症的风险增加。通过靶向可修改的血管 年轻时的因素，在大脑出现不可逆转的潜在恶化之前，我们就会说明这一点的重要性 在干预措施可能最有效的情况下，在年轻人中采取这种方法。我们将利用可靠和经过验证的 确保可再现性的措施。这项研究有很强的科学前提，并得到了充分的 动力十足。成功的保证是与参与者接触，良好的环境，以及经验和 调查人员的工作效率。

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.