Edited by: Alberto J. Espay, University of Cincinnati, USA
Reviewed by: Ron Postuma, Montreal General Hospital, Canada; Jennifer Molano, University of Cincinnati Medical Center, USA
This article was submitted to Movement Disorders, a section of the journal Frontiers in Neurology.
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Xie et al. in their article entitled “sleep drives metabolite clearance from the adult brain” in Science (342: 373–377) (
Key to understanding their paradigm is an exploration of the differences between physiological clearance of cellular waste from the central nervous system and peripheral tissues. Systemic waste interstitial proteins are transported via lymph vessels and the systemic circulation to the liver for degradation (
Xie et al. used a mouse model, with an implanted cannula for delivery of a fluorescent tracer via the cisterna magna into the CSF, to observe real-time movement of CSF
Electrocorticography (ECoG) and electromyography (EMG) determined sleep-wake status, with a sleep state practically defined as an increased power of slow waves and an awake state associated with a relative reduction in slow waves and increase in power of fast waves (
On entering sleep there was a “robust influx” of fluorescent CSF tracer along the periarterial spaces, subpial region, and into the brain parenchyma (
On awakening, CSF tracer influx reduced dramatically by 95% (
These results were replicated in a cohort of mice, examined firstly whilst awake. The intracisternal infusion of fluorescent CSF tracer was associated with only minimal influx into the brain. Then on induction of anesthesia there was a rapid influx of CSF tracer along the periarterial spaces into the brain parenchyma, similar to naturally sleeping mice (
They postulate that CSF influx into brain parenchyma is not simply a function of arterial pulsation and blood pressure but rather the interstitial space volume is dynamic and contracts during wakefulness and expands during sleep (
To test this, they used the real-time iontophoretic tetramethylammonium (TMA+) method whereby TMA+ was delivered via an iontophoresis microelectrode in the vicinity of a TMA+-sensitive microelectrode stationed approximately 150 μm away in the interstitial space. In the paradigm a small interstitial space results in reduced TMA+ dilution (as volume of interstitial space is reduced) after delivery and thus higher levels of residual TMA+ are detected by the sensing electrode (
Knowing that approximately 65% of exogenously delivered Aβ is cleared by the glymphatic system they decided to explore whether interstitial Aβ is cleared most efficiently during sleep (
There are two possible contributory factors. Either interstitial space volume is influenced by circadian rhythm or it is a function of the sleep-wake state of the individual (
Experiment | Methods | Results | Implications |
---|---|---|---|
Real-time observation of CSF influx to cerebral cortex | Infusion of fluoroscopic CSF tracer via a cannula implanted into the cisterna magna. Imaging |
When asleep: “robust influx” of fluorescent CSF tracer along the periarterial spaces, subpial regions, and parenchyma | Interstitial space volume is dynamic and a function of the state of arousal whether that be physiological states such as sleep or wakefulness or artificially induced states such as anesthesia |
When awake: CSF influx reduced “dramatically” by 95% | |||
When anesthetized: on induction there was a rapid influx of CSF similar to the sleeping state | |||
Assessment of interstitial space volume during different states of arousal (sleep, wakefulness, or anesthesia) | Iontophoretic Tetramethylammonium method (TMA+): TMA+ delivered to cortex via an iontophoresis microelectrode situated 150 μm from a TMA+ sensitive microelectrode located in the interstitial space | Interstitial space volume fraction increased by over 60% during the sleeping or anesthetized state | Confirms that interstitial space volume is dynamic and influenced by state of arousal |
Assessment of Aβ clearance during different states of arousal (sleep, wakefulness, or anesthesia) | Radiolabeled 125I-Aβ1–40 injected into the cerebral cortex. Brains harvested between 10 and 240 min after injection and residual 125I-Aβ1–40 measured | Aβ cleared twofold faster in sleeping/anesthetized mice compared to awake mice | Suggests that glymphatic efflux of waste interstitial proteins is responsive to changes in arousal state (both physiological states such as sleep and wakefulness and induced states such as anesthesia) |
Determining if interstitial space volume is influenced by arousal state or circadian rhythm | Based on the premise that wakefulness is driven by noradrenergic tone, glymphatic tracer influx was assessed (after the local administration of adrenergic antagonist) using the fluoroscopic tracer method outlined above. Furthermore, interstitial space volume was assessed in response to noradrenergic antagonist using the iontophoretic TMA+ method outlined above | Adrenergic antagonist induced an increase in CSF tracer influx “more comparable” to that seen in the sleeping/anesthetized state than that seen during wakefulness. Adrenergic antagonist resulted in significant increase in interstitial space volume fraction | Adrenergic tone has a role in modulating arousal state and the volume of the interstitial space |
Why do we need to sleep? The authors postulate that sleep is the homeostatic method responsible for the clearance of toxic metabolic byproducts accumulated during wakefulness. This study by Xie et al. raises many questions in the study of neurodegeneration. Could NA antagonists impact on the accumulation of putative toxic proteins in Alzheimer’s disease and other forms of neurodegeneration? Is rapid eye movement (REM) sleep disorder merely a manifestation of alpha synucleinopathies or could it be implicated in pathogenesis? Why do some patients with Parkinson’s disease derive sleep benefit? What causes fluctuating arousal in dementia with Lewy bodies (DLB)? Does sleep-wake state influence volumetric analysis in MRI? Given the invasive nature of the experimental methodologies used they could not be reproduced in humans in their current format, however they could provide a platform for the investigation of clearance of other neurotoxic proteins involved in neurodegeneration, using a Parkinson’s disease mouse model for example. Furthermore, they may be useful for investigation of potential drugs to promote the clearance of neurotoxic proteins, whether they be currently used adrenergic antagonist drugs or novel agents. When we try to encourage a good nights sleep for our patients perhaps we are doing them more good than we thought.