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

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.

Keywords: Alzheimer’S disease; Cerebral small vessel disease; blood-brain barrier; sleep; slow wave activity.

Figure 1

The cleaning power of a slow wave activity (SWA) during deep sleep. (a) The slow wave sleep is accompanied by increasing the interstitial fluid (ISF) volume by 60% via astrocytic-aquaporin (AQP)-channels that contributes augmentation of metabolic clearance; (b) Wakefulness reduces diffusion of metabolites by 95% via decreasing the ISF volume; (c) Alzheimer’s disease is associated with accumulation of A$\beta$ in the brain tissues due to reducing of the time of SWA and suppression of clearance of toxic protein from the brain.

Figure 2

Schematic illustration of hypothesis that the EEG characteristics of non-rapid eye movement (NREM) SWA sleep is similar for natural sleep and the blood–brain barrier (BBB) disruption due to the same mechanism of activation of clearance of metabolites and toxins such as A$\beta$ from sleeping brain and from the areas surrounding the opened BBB.

Figure 3

New breakthrough strategies targeting SWA sleep for therapy of Alzheimer’s disease (AD). (a) Alzheimer’s disease is characterized by A$\beta$-mediated reducing the time of SWA sleep; (b,c) methods of enhancement of SWA oscillations restore the time of SWA sleep and memory via improvement of glymphatic clearance of A$\beta$ from the brain.