Dysfunction of the Glymphatic System as a Potential Mechanism of Perioperative Neurocognitive Disorders

Xuli Ren, Shan Liu, Chuang Lian, Haixia Li, Kai Li, Longyun Li, Guoqing Zhao, Xuli Ren, Shan Liu, Chuang Lian, Haixia Li, Kai Li, Longyun Li, Guoqing Zhao

Abstract

Perioperative neurocognitive disorder (PND) frequently occurs in the elderly as a severe postoperative complication and is characterized by a decline in cognitive function that impairs memory, attention, and other cognitive domains. Currently, the exact pathogenic mechanism of PND is multifaceted and remains unclear. The glymphatic system is a newly discovered glial-dependent perivascular network that subserves a pseudo-lymphatic function in the brain. Recent studies have highlighted the significant role of the glymphatic system in the removal of harmful metabolites in the brain. Dysfunction of the glymphatic system can reduce metabolic waste removal, leading to neuroinflammation and neurological disorders. We speculate that there is a causal relationship between the glymphatic system and symptomatic progression in PND. This paper reviews the current literature on the glymphatic system and some perioperative factors to discuss the role of the glymphatic system in PND.

Keywords: glymphatic system; perioperative neurocognitive disorders; postoperative cognitive dysfunction; postoperative complications; postoperative neuropathy.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Ren, Liu, Lian, Li, Li, Li and Zhao.

Figures

Figure 1
Figure 1
(A) The glymphatic system is a perivascular channel formed by astrocyte end-feet throughout the brain. CSF enters the brain parenchyma through the periarterial space, exchanges with ISF, and finally exits through the perivenous space. Rapid exchange of CSF within ISF is facilitated by AQP4, which is anchored to the astrocytic end-feet. Interstitial solutes, including protein waste, are drained from the brain with CSF through the perivenous space and via the meninges and cervical lymphatics. (B) Dysfunction of the perioperative glymphatic system. Perioperative anesthetic drugs can cause hemodynamic changes that reduce arterial pulsation mechanism change and decrease the inflow of the glymphatic system. Surgically induced systemic inflammation can cause blood-brain barrier opening and glymphatic system damage, leading to neuroinflammation and decreased waste clearance. Both the entry of peripheral inflammatory substances and the accumulation of protein wastes in the brain, such as Aβ accumulation and folding, can activate astrocytes and microglia and trigger neuroinflammation. Neuroinflammation can worsen the damage to the function and structure of the glymphatic system. Forceful expiration, positive pressure ventilation, and prone position can cause a decrease in venous return, leading to a decrease in CSF clearance. Pain, preoperative stress, and sleep disturbances can affect both CSF inflow and clearance. Glymphatic dysfunction can lead to a more significant accumulation of protein and waste products, which can trigger neuroinflammation and lead to PND. PVC, Perivascular space.
Figure 2
Figure 2
In this model, the glymphatic system resides at the intersection of a broad scope of perioperative risk factors, which share an association with diminished brain waste clearance. Individual factors are preexisting impairments in glymphatic function prior to surgery; anesthetic and surgical factors are associated with a dramatic decline in perioperative glymphatic function, compromising the glymphatic system and exacerbating the progression of preexisting disease. Glymphatic system dysfunction, in turn, contributes to protein aggregation and misfolding, leading to neuroinflammation, neurodegeneration, and ultimately PND.

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