Sleep Deprivation Impairs Molecular Clearance From the Human Brain

Per Kristian Eide; Vegard Vinje; Are Hugo Pripp; Kent-Andre Mardal; Geir Ringstad

Disclosures

Brain. 2021;144(3):863-874. 

In This Article

Abstract and Introduction

Abstract

It remains an enigma why human beings spend one-third of their life asleep. Experimental data suggest that sleep is required for clearance of waste products from brain metabolism. This has, however, never been verified in humans. The primary aim of the present study was to examine in vivo whether one night of total sleep deprivation affects molecular clearance from the human brain. Secondarily, we examined whether clearance was affected by subsequent sleep. Multiphase MRI with standardized T1 sequences was performed up to 48 h after intrathecal administration of the contrast agent gadobutrol (0.5 ml of 1 mmol/ml), which served as a tracer molecule. Using FreeSurfer software, we quantified tracer enrichment within 85 brain regions as percentage change from baseline of normalized T1 signals. The cerebral tracer enrichment was compared between two cohorts of individuals; one cohort (n = 7) underwent total sleep deprivation from Day 1 to Day 2 (sleep deprivation group) while an age and gender-matched control group (n = 17; sleep group) was allowed free sleep from Day 1 to Day 2. From Day 2 to 3 all individuals were allowed free sleep. The tracer enriched the brains of the two groups similarly. Sleep deprivation was the sole intervention. One night of sleep deprivation impaired clearance of the tracer substance from most brain regions, including the cerebral cortex, white matter and limbic structures, as demonstrated on the morning of Day 2 after intervention (sleep deprivation/sleep). Moreover, the impaired cerebral clearance in the sleep deprivation group was not compensated by subsequent sleep from Day 2 to 3. The present results provide in vivo evidence that one night of total sleep deprivation impairs molecular clearance from the human brain, and that humans do not catch up on lost sleep.

Introduction

Sleep is essential for human life, including cognitive function (Rasch and Born, 2013), but it remains a mystery why man spends about one-third of life asleep. Experimental evidence has shown that sleep has a restorative function by facilitating clearance of metabolic waste products from the brain that accumulate during wakefulness (Xie et al., 2013). With two-photon microscopy, it was found that sleep increased the brain interstitial volume fraction by 60%, allowing for a 2-fold faster clearance of amyloid-β from the cortex. The observations echoed with reports of disrupted sleep in the preclinical stage of Alzheimer's disease (Moran et al., 2005), a disease in which amyloid-β and tau aggregation in susceptible brain areas develop long before onset of clinical dementia. Severe sleep disturbances also accompany traumatic brain injury (Mathias and Alvaro, 2012), where patients suffer from increased cerebral tau and amyloid-β burden and risk of Alzheimer's disease (Johnson et al., 2012). It was previously demonstrated in a mouse Alzheimer's disease model that interstitial levels of amyloid-β, a metabolic by-product of neuronal activity, increased after acute sleep deprivation, while chronic sleep deprivation increased amyloid-β formation (Kang et al., 2009). Others also reported that sleep deprivation increased the amount of soluble amyloid-β and the risk of amyloid-β plaque formation in mice (Roh et al., 2012). The levels of tau were also increased in the interstitial fluid of the hippocampus following sleep deprivation (Holth et al., 2019). In healthy humans, undisturbed sleep caused 6% reduction in CSF amyloid-β42 levels while remaining unchanged after one night of total sleep deprivation (Ooms et al., 2014). An amyloid-β PET study showed that one night of sleep deprivation increased parenchymal amyloid-β burden by 5% in 20 healthy individuals (Shokri-Kojori et al., 2018). More recently, a direct link between sleep-related neuronal activity and CSF and blood flow was indicated based on observations that slow-wave sleep was accompanied with large-amplitude CSF flow as compared with the awake state, and an inverse relationship between CSF flow and blood flow (Fultz et al., 2019). It has, however, never been demonstrated in vivo whether sleep, or sleep deprivation, affects molecular clearance from the human brain.

The present study was undertaken to examine the effect of one night of total sleep deprivation on molecular clearance from the human brain. The MRI contrast agent gadobutrol (Gadovist®, Bayer) was used as tracer molecule to enrich brain tissue via intrathecal administration in CSF (Ringstad et al., 2018). Gadobutrol is a highly hydrophilic molecule with molecular weight of 604 Da, hydraulic diameter of ~2 nm; and distributes freely within the brain, confined to the extravascular compartment by the blood–brain barrier (Ringstad et al., 2018). Gadobutrol as a CSF tracer may therefore be considered a surrogate marker for assessing transport of water-soluble metabolites excreted along extravascular pathways within the brain, including amyloid-β and tau. The MRI research protocol included standardized T1-weighted MRI scanning before and after intrathecal gadobutrol at predefined time points during Day 1 and at 24 h (next morning), 48 h (the morning after) and at 4 weeks (Supplementary Figure 1). Following completion of imaging, the entire brain was analysed in FreeSurfer, allowing for the assessment of 85 subregions.

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