Sleep as a Novel Biomarker and a Promising Therapeutic Target for Cerebral Small Vessel Disease: A Review Focusing on Alzheimer's Disease and the Blood-Brain Barrier.

Oxana Semyachkina-Glushkovskaya,Dmitry Postnov,Jürgen Kurths,Thomas Penzel

doi:10.3390/ijms21176293

Abstract

Cerebral small vessel disease (CSVD) is a leading cause of cognitive decline in elderly people and development of Alzheimer’s disease (AD). Blood–brain barrier (BBB) leakage is a key pathophysiological mechanism of amyloidal CSVD. Sleep plays a crucial role in keeping health of the central nervous system and in resistance to CSVD. The deficit of sleep contributes to accumulation of metabolites and toxins such as beta-amyloid in the brain and can lead to BBB disruption. Currently, sleep is considered as an important informative platform for diagnosis and therapy of AD. However, there are no effective methods for extracting of diagnostic information from sleep characteristics. In this review, we show strong evidence that slow wave activity (SWA) (0–0.5 Hz) during deep sleep reflects glymphatic pathology, the BBB leakage and memory deficit in AD. We also discuss that diagnostic and therapeutic targeting of SWA in AD might lead to be a novel era in effective therapy of AD. Moreover, we demonstrate that SWA can be pioneering non-invasive and bed–side technology for express diagnosis of the BBB permeability. Finally, we review the novel data about the methods of detection and enhancement of SWA that can be biomarker and a promising therapy of amyloidal CSVD and CSVD associated with the BBB disorders.

Highlights

Why do we need to sleep and how long should we sleep? Such very highly active people as Margaret Thatcher resent the idea of spending one third of their lives asleep and train themselves to get by with significantly less sleep than others
The poor sleep quality and short sleep duration are associated with increased Aβ deposition Clinical studies have shown that Aβ content in CSF is lower in sleep than wakefulness There is evidence that Aβ clearance is increased during sleep due to increased interstitial fluid (ISF) bulk flow [9]
An key pathophysiological mechanism of Cerebral small vessel disease (CSVD) is blood–brain barrier (BBB) leakage leading to progression of CSVD

Summary

Sleep as a Potential Biomarker of Alzheimer’S Disease

Why do we need to sleep and how long should we sleep? Such very highly active people as Margaret Thatcher resent the idea of spending one third of their lives asleep and train themselves to get by with significantly less sleep than others. Studies in animal models have found decreased SWA in P301S tau transgenic mice [34] Both young and adult mice with a model of amyloidosis (APPswePS1dE9) demonstrate decrease in the cortical SWA power but not frequency with significantly reducing the time of NREM sleep [35,36]. Why SWA reflects AD pathology remains unknown but there is strong evidence that it can be related to recently discovered correlation between SAW and activation of glymphatic clearance during deep sleep [24]. The impaired CSF and ISF flow during sleep deficit can contribute to the reduced glymphatic fluid transport. Especially SWA, are closely associated with reducing of glymphatic clearance of metabolites and toxins such as Aβ that can be an important informative platform for development of new promising strategies in early diagnosis of AD (Figure 1)

Slow Wave Activity as a Biomarker of Disruption of Blood–Brain Barrier

Slow Sleep Wave Enhancement Is Promising Therapy of Alzheimer’S Disease

Findings

Conclusions