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，神经退行性疾病与大量的 睡眠中断睡眠中断现在被认为不仅是神经退化的症状， 也可能导致疾病的发生。值得注意的是，阿尔茨海默病的病理学与 在非快速眼动（NREM）睡眠期间EEG慢波丢失。睡眠被认为是重要的 用于将蛋白质如淀粉样蛋白-β和tau从脑清除到脑脊液（CSF）中，和 人脑在NREM睡眠期间显示出CSF流动的波，这表明睡眠期间的CSF流动可能 在影响大脑健康方面发挥作用。这项提议旨在了解神经慢波之间的联系 在健康老龄化和阿尔茨海默病风险个体的睡眠和脑脊液流动中。我们假设 神经活动可以通过影响脑血容量来诱导CSF流动。我们反过来预测， 衰老大脑睡眠期间神经慢波的丧失可能导致睡眠依赖性CSF流量的丧失， 这种下降与阿尔茨海默病的遗传风险因素有关。为了验证我们的假设，我们将使用 多模式成像，以同时测量神经活动、血液动力学和CSF流量。我们将测试 神经活动和CSF流量之间的联系，并将确定老年人睡眠慢波的下降是否与年龄有关。 成年人与脑脊液流量减少有关。我们将进一步研究这一过程是否更为严重， 在具有阿尔茨海默病遗传风险的健康老年人中被破坏。总之，这些研究将建立 一种生物学机制来解释衰老过程中睡眠的改变如何导致流体流动动力学的改变， 将为未来生物标志物和干预措施的开发奠定重要基础， 调节老化大脑中的脑脊液流量。

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.