Sleep-dependent modulation of cerebrospinal fluid flow in aging

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.