One night of sleep deprivation reduces spatially patterned human brain clearance: implications for simulated tau propagation

Abstract

Neurotoxic protein fragments such as amyloid-beta and tau accumulate in characteristic staging patterns in Alzheimer's disease. The brain clears such substances via multiple systems, including the extracellular-extravascular route known as glymphatic clearance, but how such clearance is distributed across the brain, how this distribution is affected by sleep, and its implications for neurodegenerative disease progression remain unclear. Using Bayesian inference to fit a kinetic model of enhancement and clearance to longitudinal CSF tracer-enhanced MRI, we estimate CSF tracer clearance rates for every connectome region in 21 subjects. We find that clearance is spatially patterned across the living human brain and consistent between subjects. Clearance rates are amongst the highest in the entorhinal cortex and decrease across regions in Braak stage order. One night of sleep deprivation reduces mean clearance levels while leaving the spatial pattern largely unchanged. To study how mean clearance level and spatial pattern affect tau propagation in silico, we use the CSF tracer clearance rates as a proxy for regional tau clearance in a computational model of protein accumulation, spread, and regional damage. Across subject-specific simulations, clearance level and spatial pattern have distinct effects on tau propagation. The clearance level determines the timescale of simulated pathology, while the spatial pattern shapes its accumulation and onset. These results identify CSF tracer clearance as a spatially organised property of the human brain that is reduced by sleep deprivation, and suggest that its overall level and regional organisation may independently shape the timing and spatial progression of neurodegenerative proteinopathy.