Effect of Suvorexant on Alzheimer's Disease Biomarkers

项目总结 睡眠障碍日益被认为是阿尔茨海默病(AD)的危险因素和 阿尔茨海默病病理学。睡眠-觉醒周期影响脑脊液(CSF)浓度 阿尔茨海默病发病机制的关键蛋白质。我们最近报告称，夜间睡眠中断 通过增加产量/释放，脑脊液淀粉样蛋白-β(A-β)水平增加约30%。食欲素(又称食欲素 下丘脑)是一种促进觉醒的神经肽。一种双重增食欲素受体拮抗剂的长期应用 (DORA)增加淀粉样前体蛋白(APP)转基因小鼠的睡眠既降低了可溶性 间质液中Aβ的浓度与淀粉样斑块的形成我们的初步数据显示，一只朵拉， 可显著降低磷酸化tau-181(PT181)与非磷酸化tau-181的比率 (T181)。尽管之前的研究考察了睡眠对脑脊液Aβ和tau的影响，但它 目前尚不清楚长期服用DORA如何影响血浆和脑脊液tau、磷酸化tau(p-tau)、Aβ、 以及其他阿尔茨海默病液体生物标记物在阿尔茨海默病病理个体中的应用。在这个项目中，我们将 验证假设，慢性治疗6个月会降低脑脊液pT181/T181和 其他脑脊液和血浆AD生物标志物。在这个项目中，我们将使用创新的适应性试验设计来测试 使用Suvorexant进行慢性治疗以二级预防阿尔茨海默病的可能性。认知能力为200 年龄为≥65岁的正常、淀粉样阳性、有症状的失眠成年人将随机接受 安慰剂或Suvorexant治疗6个月。每个参与者都将接受多导睡眠图以及腰椎和 分别于基线、3个月和6个月采脑脊液和血样。我们将检验这一假设 超立克星长期治疗会降低脑脊液pT181/T181，并影响脑脊液的功能 血浆A型β、脑脊液和血浆tau、其他形式的脑脊液和血浆p-tau，以及用于免疫的脑脊液标志物 神经元变性的反应(小胶质细胞功能)、突触功能和非tau指标。最优试验 在启动具有最大成功机会的完全二级预防试验之前，设计是必不可少的。这 这项研究将为设计阿尔茨海默病二级预防试验提供关键信息 SUVERREXANT获取关于SUVREXANT的药代动力学、安全性和慢性作用的数据 阿尔茨海默病生物标记物。

PROJECT SUMMARY Sleep disturbances are increasingly recognized as a risk factor for Alzheimer’s disease (AD) and a marker for Alzheimer’s disease pathology. The sleep-wake cycle affects the cerebrospinal fluid (CSF) concentrations of proteins critical to Alzheimer’s disease pathogenesis. We recently reported that overnight sleep disruption increases CSF amyloid-β (Aβ) levels by ~30% via increased production/release. Orexins (also called hypocretins) are wake-promoting neuropeptides. Chronic administration of a dual orexin receptor antagonist (DORA) to increase sleep in amyloid precursor protein (APP) transgenic mice decreased both the soluble concentration of Aβ in interstitial fluid and amyloid plaque formation. Our preliminary data shows that a DORA, suvorexant, acutely decreases the ratio of phosphorylated tau-181 (pT181) to unphosphorylated tau-181 (T181) in CSF. Although previous studies examined sleep-mediated changes in CSF Aβ and tau over hours, it is unknown how chronic administration of DORAs affect plasma and CSF tau, phosphorylated tau (p-tau), Aβ, and other Alzheimer’s disease fluid biomarkers in individuals with Alzheimer’s pathology. In this project, we will test the hypothesis that chronic treatment with suvorexant for 6 months will decrease CSF pT181/T181 and other CSF and plasma AD biomarkers. In this project, we will use an innovative adaptive trial design to test the potential of chronic treatment with suvorexant for secondary prevention of Alzheimer’s disease. 200 cognitively normal, amyloid-positive adults with symptomatic insomnia age ≥65 years will be randomized to receive placebo or suvorexant for 6 months. Each participant will undergo polysomnography as well as lumbar and venous puncture to sample CSF and blood at baseline, 3 months, and 6 months. We will test the hypothesis that chronic treatment with suvorexant will decrease CSF pT181/T181 as well as determine the effect on CSF plasma Aβ, CSF and plasma tau, other forms of CSF and plasma p-tau, and CSF markers for immune response (microglial function), synaptic function, and non-tau measures of neuronal degeneration. Optimal trial design is essential prior to launching a full secondary prevention trial with a maximum chance of success. This study will provide critical information for designing Alzheimer’s disease secondary prevention trial using suvorexant obtaining data on pharmacokinetics, safety, and chronic effects of suvorexant on multiple soluble Alzheimer’s disease biomarkers.