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Introduction The glymphatic system facilitates solute transport through the exchange of cerebral spinal fluid (CSF) and interstitial fluids using a brain-wide system of perivascular spaces. Such exchange is primarily active during sleep. Aging and sleep disruptions have been shown to decrease glymphatic clearance and increase risk of cognitive impairment. Here, we used phase contrast MRI (PC MRI) to measure CSF egress from the Aqueduct of Sylvius (AoS) as a marker of CSF circulation in the setting of sleep deprivation and aging. Methods Under approved IRB protocols six young adults (22±3 yo, 4F) underwent a night of full sleep and a night of sleep deprivation in a 3T Philips Ingenia Elition scanner with a 32-channel head coil. Additionally, six older adults (66±3 yo, 2F) were scanned using identical MRI protocol but only after full sleep. The PC MRI was a single slice acquisitions with 14 samples within a cardiac cycle. The slice was perpendicular to the AoS and care was taken to avoid any phase wrapping. All individuals also completed the General Practitioner’s assessment of cognition (GPCOG) in the morning prior to their scan. CSF velocity in cm/s was calculated from the phase data. Heart rate (HR) was recorded during the scan using a pulse-oximeter. Results CSF velocity was numerically lower after sleep deprivation (2.6±2.1 cm/s) than after a night of full sleep (3.1±2.0 cm/s) in young adults, but the difference was not significant. CSF velocity in the older adults was lower (2.0□0.5 cm/s, marginally significant at p = 0.10) than in young adults. HR in older adults (59±6) was significantly lower than the young adults under both conditions (full sleep: 68±4, sleep deprivation: (66±11) and, across all participants, HR was weakly correlated (r=-0.35) with CSF velocity. GPCOG was not significantly different across conditions or groups. Conclusion Although only marginally significant, CSF velocity in the AoS, measured by PC MRI is sensitive to HR variations and aging but not to sleep. Continued investigation with a larger sample size is underway to understand if these preliminary observations hold and if CSF velocity in the AoS is associated with glymphatic transport. Support (if any)

Introduction Recent studies have found that mid-life sleep disruption is associated with the development of Alzheimer’s disease-related neuropathology, including the deposition of amyloid beta. Yet, the mechanism connecting sleep disruption, particularly over chronic timescales, and downstream Alzheimer’s pathology remains unclear. Methods In this study, we evaluated the impact chronic sleep disruption has on the development of neuroinflammation and amyloid beta plaques in the 5xFAD amyloidosis mouse model. Chronic sleep disruption in male and female C57BL/6 and 5xFAD+ mice was performed in Lafayette sleep fragmentation cages from 10-18 weeks of age. Glymphatic function was assessed by measuring the influx of fluorescent cerebrospinal fluid tracers into brain tissue. Aquaporin-4 localization, amyloid-beta plaque deposition, and markers of astroglial and microglial activation were assessed by immunofluorescence. Results We observed that chronic sleep disruption increased neuropathological outcomes in 5xFAD+ and littermate controls. This was evident in significantly increased amyloid-beta plaque deposition and significantly increased gliosis, indicated by increases in both astrocyte (GFAP) and microglial (Iba1) expression. The impact on glymphatic function, evaluated through both cerebrospinal fluid tracer distribution and assessment of aquaporin-4 mislocalization, was assessed in parallel and correlated with neuropathological outcomes. Conclusion These findings highlight the critical association between dysfunctional sleep and the development of Alzheimer’s-related amyloid beta pathology. They indicate that there is an interaction between chronic sleep disruption, neuroinflammation, and amyloid □ deposition. Support (if any)

Introduction Recent studies suggest a bidirectional relationship between sleep disruption and Alzheimer’s disease, with mid-life sleep disruption associated with the development of Alzheimer’s-related amyloid and tau pathology. Yet, the mechanistic link between sleep disruption, particularly over chronic time scales, and the development of Alzheimer’s pathology remains unclear. Methods In this study, we evaluated the impact chronic sleep disruption has on the onset of cognitive impairment and neuropathologic disease progression using the 5xFAD amyloidosis mouse model. Chronic sleep disruption in male and female C57BL/6 and 5xFAD+ mice was performed in Lafayette sleep fragmentation cages from 10-18 weeks of age. Cognitive impairment was evaluated through behavioral tasks indicative of spatial memory, short-term memory, locomotion, anxiety, and activities of daily living. Upon completion of behavioral experiments, glymphatic function was assessed by measuring the influx of fluorescent cerebrospinal fluid tracers into brain tissue. Aquaporin-4 localization, amyloid plaque deposition, and markers of astroglial and microglial activation were assessed by immunofluorescence. Results We observed that chronic sleep disruption impaired cognitive performance and increased neuropathological outcomes in 5xFAD+ and littermate controls. The impact on glymphatic function was assessed in parallel and correlated with neuropathological and behavioral outcomes. Conclusion These findings highlight the critical association between dysfunctional sleep and the development of cognitive impairment and neuropathologic disease progression. They indicate that there is a potential interaction between inflammatory expression after chronic sleep disruption and neuropathologic disease progression. Support (If Any)