A novel conceptual framework for the functionality of the glymphatic system

Author: Kyriaki Astara1,2, Christina Pournara1, Edoardo Rosario de Natale3, Heather Wilson3, George D Vavougios4,5, Andreas S Lappas1,6, Marios Politis3, Nikos G Christodoulou1,7
1 Department of Psychiatry, Faculty of Medicine, University of Thessaly, Larissa, Greece.
2 Department of Neurology, 417 Army Equity Fund Hospital (NIMTS), Athens, Greece.
3 Neurodegeneration Imaging Group, University of Exeter Medical School, London, United Kingdom.
4 Department of Neurology, Faculty of Medicine, University of Cyprus, Lefkosia, Cyprus.
5 Department of Neurology, Athens Naval Hospital, Athens, Greece.
6 Aneurin Bevan University Health Board, Wales, United Kingdom.
7 Medical School, University of Nottingham, Nottingham, United Kingdom.
Conference/Journal: J Neurophysiol
Date published: 2023 Apr 19
Other: Special Notes: doi: 10.1152/jn.00360.2022. , Word Count: 249

The glymphatic system is responsible for the clearance of the potentially harmful metabolic waste of the Central Nervous System. The prevalent theory is that the cerebrospinal fluid (CSF) circulates in the perivascular space (PVS) and through the astrocytes' aquaporin-4 channels (AQ-4), and it is then drained by the lymphatic vessels after mixing with interstitial fluid (ISF). However, there is little evidence supporting this hypothesis. A deeper understanding of the physiology of the glymphatic system could transform the way we understand neuropathology and our approach to treating neurological and neuropsychiatric disorders. In this review, we introduce a new conceptual framework for the functionality of the glymphatic system, offering new directions for future research. We propose that CSF and ISF exchange flow depends on arterial pulsation, respiration, posture and sleep. PVS changes due to disrupted cerebral autoregulation, alternations of intrathoracic pressure, venous flow and body position can also influence the glymphatic flow. The role of respiration remains controversial due to the variety of parameters that interfere with glymphatic functionality. Slow-wave sleep is important for glymphatic clearance due to neuronal electromagnetic synchronization and expansion of the interstitial space. Therefore, sleep and vascular disorders, as well as ageing, may hinder glymphatic flow and induce a noxious milieu of susceptibility to neurodegenerative disorders because of metabolic waste accumulation. We lastly introduce a new idea postulating that electromagnetic induction may constitute one of the propelling forces for the convectional current and mixing of CSF and ISF.

Keywords: cerebral autoregulation; glymphatic; respiration; sleep.

PMID: 37073982 DOI: 10.1152/jn.00360.2022