Sleep-dependent modulation of cerebrospinal fluid flow in aging and across genetic risk for Alzheimers disease

项目摘要 睡眠对大脑健康至关重要，而神经退行性疾病与大量 睡眠障碍。睡眠障碍现在被认为不仅是神经退化的症状，而且 可能也会导致这种疾病的发生。值得注意的是，阿尔茨海默病的病理与 在非快速眼动(NREM)睡眠期间脑电慢波消失。睡眠被认为是很重要的 用于将淀粉样β蛋白和tau等蛋白质从大脑清除到脑脊液(CSF)中，以及 人类大脑在NREM睡眠期间表现出脑脊液流动的波，这表明睡眠期间的脑脊液流动可能 在其对大脑健康的影响中发挥作用。这项提议旨在了解神经慢波之间的联系。 在睡眠和脑脊液流动期间，健康老龄化和阿尔茨海默病高危人群。我们假设 这种神经活动可以通过影响脑血容量来诱导脑脊液流动。我们反过来又预测 在老化的大脑中，睡眠期间神经慢波的丢失可能会导致睡眠依赖的脑脊液流量的丧失，并且 这种下降与阿尔茨海默病的遗传风险因素有关。为了检验我们的假设，我们将使用 多模式成像可同时测量神经活动、血流动力学和脑脊液流量。我们将测试 神经活动和脑脊液流量之间的联系，并将确定老年人睡眠慢波是否下降 成人的脑脊液流量较少。我们将进一步研究这一过程是否更加严重 在有阿尔茨海默病遗传风险的健康老年人中被破坏。总之，这些研究将确立 衰老过程中睡眠改变如何导致体液流动动力学改变的生物学机制，以及这一知识 将为开发未来的生物标志物和干预措施奠定必要的基础，以评估和 调节老化大脑中的脑脊液流动。

Project Abstract Sleep is essential for brain health, and neurodegenerative diseases are associated with substantial sleep disruptions. Disrupted sleep is now thought to not just be a symptom of neurodegeneration, but potentially to also contribute to the onset of the disease. Notably, Alzheimer’s disease pathology is associated with loss of EEG slow waves during non-rapid eye movement (NREM) sleep. Sleep is thought to be important for clearance of proteins such as amyloid-beta and tau from the brain into the cerebrospinal fluid (CSF), and the human brain exhibits waves of CSF flow during NREM sleep, suggesting that CSF flow during sleep may play a role in its effects on brain health. This proposal aims to understand the link between neural slow waves during sleep and CSF flow in healthy aging and in individuals at risk for Alzheimer’s disease. We hypothesize that neural activity can induce CSF flow through its effects on cerebral blood volume. We in turn predict that loss of neural slow waves during sleep in the aging brain may lead to loss of sleep-dependent CSF flow, and that this decline is associated with Alzheimer’s disease genetic risk factors. To test our hypothesis, we will use multimodal imaging to simultaneously measure neural activity, hemodynamics, and CSF flow. We will test the link between neural activity and CSF flow, and will identify whether the decline in sleep slow waves in older adults is associated with less CSF flow. We will further examine whether this process is more severely disrupted in healthy older adults with genetic risk for Alzheimer’s disease. Together, these studies will establish a biological mechanism for how altered sleep in aging leads to altered fluid flow dynamics, and this knowledge will form an essential foundation for the development of future biomarkers and interventions to evaluate and modulate CSF flow in the aging brain.