Increased Cerebrospinal Fluid Amyloid-ß During Sleep Deprivation in Healthy Middle-Aged Adults Is Not Due to Stress or Circadian Disruption.

BACKGROUND: Concentrations of soluble amyloid-ß (Aß) oscillate with the sleep-wake cycle in the interstitial fluid of mice and cerebrospinal fluid (CSF) of humans. Further, the concentration of Aß in CSF increases during sleep deprivation. Stress and disruption of the circadian clock are additional mechanisms hypothesized to increase CSF Aß levels. Cortisol is a marker for stress and has an endogenous circadian rhythm. Other factors such as glucose and lactate have been associated with changes in sleep-wake activity and/or Aß. OBJECTIVE: In this exploratory study, we used samples collected in a previous study to examine how sleep deprivation affects Aß, cortisol, lactate, and glucose in plasma and CSF from healthy middle-aged adults (N = 11). METHODS: Eleven cognitively normal participants without evidence of sleep disturbance were randomized to sleep deprivation or normal sleep control. All participants were invited to repeat the study. Cortisol, lactate, glucose, and Aß were measured in 2-h intervals over a 36-h period in both plasma and CSF. All concentrations were normalized to the mean prior to calculating mesor, amplitude, acrophase, and other parameters. RESULTS: One night of sleep deprivation increases the overnight concentration of Aß in CSF approximately 10%, but does not significantly affect cortisol, lactate, or glucose concentrations in plasma or CSF between the sleep-deprived and control conditions. CONCLUSION: These data suggest that sleep deprivation-related changes in CSF Aß are not mediated by stress or circadian disruption as measured by cortisol.

Effect of sleep on overnight cerebrospinal fluid amyloid ß kinetics.

Sleep disturbances are associated with future risk of Alzheimer disease. Disrupted sleep increases soluble amyloid ß, suggesting a mechanism for sleep disturbances to increase Alzheimer disease risk. We tested this response in humans using indwelling lumbar catheters to serially sample cerebrospinal fluid while participants were sleep-deprived, treated with sodium oxybate, or allowed to sleep normally. All participants were infused with 13 C6 -leucine to measure amyloid ß kinetics. We found that sleep deprivation increased overnight amyloid ß38, amyloid ß40, and amyloid ß42 levels by 25 to 30% via increased overnight amyloid ß production relative to sleeping controls. These findings suggest that disrupted sleep increases Alzheimer disease risk via increased amyloid ß production. Ann Neurol 2018;83:197-204.