Effect of sleep on overnight cerebrospinal fluid amyloid β kinetics

Abstract

Sleep disturbances are associated with future risk of Alzheimer disease. Disrupted sleep increases soluble amyloid β, 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 β kinetics. We found that sleep deprivation increased overnight amyloid β38, amyloid β40, and amyloid β42 levels by 25 to 30% via increased overnight amyloid β production relative to sleeping controls. These findings suggest that disrupted sleep increases Alzheimer disease risk via increased amyloid β production. Ann Neurol 2018;83:197-204.

Figure 1. Overnight CSF Aβ kinetics

Eight subjects participated in the study. Four participants completed the control, the sleep-deprived, and sleep-induced intervention groups. Four participants completed two groups. A–C: All Aβ38, Aβ40, and Aβ42 concentrations were normalized to the baseline 07:00–19:00. The overnight period during the intervention night was defined as hours 18–28 (01:00–11:00) to account for transit time of CSF from the brain to lumbar catheter (shaded). Sleep deprivation increased overnight Aβ by 30% over the baseline compared to participants in the control and sleep-induced groups, however the control and sleep-induced groups were not significantly different. D–F: Aβ peptide enrichments were normalized to each subject’s plasma leucine enrichment plateau. The shape of the normalized SILK curves were similar between groups for Aβ38, Aβ40, and Aβ42. G–H: Aβ38/40 and Aβ42/40 isotopic enrichment ratios from hours 18–36 (01:00–19:00). I: Fractional turnover rates (FTR) for Aβ38, Aβ40, and Aβ42 were not significantly different between groups. Blue=control; Red=sleep-deprived; Green=sleep-induced. Error bars indicate standard error. The vertical dashed line is both the time of ¹³C₆-leucine infusion and the intervention start time. The horizontal dashed line is at 100% of baseline. *p<0.0001.

Figure 2. Within-subject changes in Aβ40 from baseline

4 participants completed the control (blue), sleep-deprived (red), and sleep-induced (green) intervention groups (A–D). 4 participants completed two groups (E–H). All Aβ40 concentrations were normalized to the baseline 07:00–19:00. The overnight period during the intervention night was defined as hours 18–28 (01:00–11:00) to account for transit time of CSF from the brain to lumbar catheter (shaded). The vertical dashed line is both the time of ¹³C₆-leucine infusion and the intervention start time. The horizontal dashed line is at 100% of baseline.

Figure 3

Aβ SILK model sensitivity analyses. Stable isotope labeling kinetic (SILK) modeling of normalized mole fraction labeled of Aβ40 from one participant was performed (black). A. All model parameters were held constant except for production rate. Production rate was changed to 199% (green) and 1% of the nominal production rate (red). Production rate did not alter the best model fit of the SILK data and the labeling curves are identical. B. All model parameters were held constant except for fractional turnover rate (FTR). FTR was changed to 105% (green) and 95% (red) of the nominal FTR. Increased FTR by 5% results in a higher and earlier peak (green dashed line) compared to decreasing FTR by 5% (red dashed line). C. All model parameters were held constant except for fractional turnover rate (FTR). FTR was changed to 120% (green) and 80% (red) of the nominal FTR. Increased FTR results in a higher, narrower, and earlier peak (green dashed line) while decreased FTR delayed peak onset and widened the labeling curve (red dashed line).