A Comprehensive Review of the Glymphatic System and Sleep, Methodological Comparisons, and Future Advancements in Dementia Research

Abstract Dementia is the seventh leading cause of death globally, and yet there is no cure for these diseases because of the biological complexity of the brain and the delayed diagnoses of many patients. Several advancements in the field of neuroscience have been made to further understand the brain and its systems, including the groundbreaking discovery of the glymphatic system by Dr. Nedergaard and her team. The glymphatic system supports the brain’s clearance of metabolic waste, including key pathogenic proteins, Tau and Aβ, involved in neurodegeneration. Specifically, it is a specialized pathway that exchanges cerebrospinal fluid and interstitial fluid through aquaporin-4 water channels located on the astrocytic endfeet. Although foundational models by Xie et al. (2013) suggested that interstitial volume expands and a higher amount of metabolic waste is flushed out during deep sleep, differential findings by Miao et al. (2024) proposed that glymphatic clearance is reduced during slow-wave sleep and increased during wakefulness. Nevertheless, the two major experiments differed in results because of their different injection sites, and thus, Miao et al. (2024) measured the displacement of metabolic waste between sections of the brain, while Xie et al. (2014) measured the CSF efflux along arterial routes. While intrathecal MRI, an advancing technology, has confirmed perivascular transport in humans, there is a lack of non-invasive and effective imaging techniques that can be used to trace CSF in the brain as scientists have done in rodents. This review synthesizes current insights of the glymphatic system, addresses contesting methodological perspectives, and discusses the current and future possibilities in imaging modalities to encapsulate the research done on the glymphatic system and to advance diagnostic strategies for dementia. Ultimately, the glymphatic system is a crucial mechanism that clears metabolic waste and, along with sleep, plays an important role in neurodegeneration, but further advancements in non-invasive imaging and understanding the relationship between sleep and fluid clearance are essential to apply this research in patient care.