In a recent review article titled “A new look at cerebrospinal fluid circulation”, Brinker et al. comprehensively described novel insights from molecular and cellular biology as well as neuroimaging research, which indicate that cerebrospinal fluid (CSF) physiology is much more complex than previously believed. The glymphatic system is a recently defined brain-wide paravascular pathway for CSF and interstitial fluid exchange that facilitates efficient clearance of interstitial solutes, including amyloid-β, from the brain. Although further studies are needed to substantiate the functional significance of the glymphatic concept, one implication is that glymphatic pathway dysfunction may contribute to the deficient amyloid-β clearance in Alzheimer’s disease. In this paper, we review several lines of evidence suggesting that the glymphatic system may also have potential clinical relevance for the understanding of glaucoma. As a clinically acceptable MRI-based approach to evaluate glymphatic pathway function in humans has recently been developed, a unique opportunity now exists to investigate whether suppression of the glymphatic system contributes to the development of glaucoma. The observation of a dysfunctional glymphatic system in patients with glaucoma would provide support for the hypothesis recently proposed by our group that CSF circulatory dysfunction may play a contributory role in the pathogenesis of glaucomatous damage. This would suggest a new hypothesis for glaucoma, which, just like Alzheimer’s disease, might be considered then as an imbalance between production and clearance of neurotoxins, including amyloid-β.

Evidence of a link between Alzheimer’s disease (AD) and glaucoma has emerged from studies showing that patients with AD may have a significantly increased rate of glaucoma occurrence. In addition, it has been reported that patients with AD exhibit optic nerve degeneration and loss of retinal ganglion cells. In spite of intensive research, the clinical and genetic relationships between AD and glaucoma remain obscure. It is unclear whether the clinical correlation between the two diseases might be due to shared risk factors or the influence of one disorder on the other. Interestingly, certain observations may provide a clue towards a better understanding of the high rate of comorbidity reported between AD and glaucoma. In this article, we hypothesise that there may be a causal relationship between AD and glaucoma that may be explained by decreased cerebrospinal fluid pressure (CSFP) in patients with AD. A very recent study reported the intriguing new observation that mean CSFP was 33% lower in subjects with primary open-angle glaucoma than that of non-glaucomatous controls. It was noted that this observation supports the concept that an abnormal high trans-lamina cribrosa pressure difference, whether the result of elevated intraocular pressure, reduced CSFP, or both, plays an important role in glaucomatous optic nerve damage. Interestingly, it was also reported that a substantial proportion of AD patients have very low CSFP. Therefore, we hypothesise that an abnormal high trans-lamina cribrosa pressure difference may explain why patients with AD have a greater risk for developing glaucoma.

The underlying pathophysiology of primary open‐angle glaucoma remains unclear, but the lamina cribrosa seems to be the primary site of injury, and raised intraocular pressure is a major risk factor. In recent years, a decreased intracranial pressure, leading to an abnormally high trans‐lamina cribrosa pressure difference, has gained interest as a new risk factor for glaucoma. New research now lends support to the hypothesis that a paravascular transport system is present in the eye analogous to the recently discovered ‘glymphatic system’ in the brain, which is a functional waste clearance pathway that promotes elimination of interstitial solutes, including β‐amyloid, from the brain along paravascular channels. Given that β‐amyloid has been reported to increase by chronic elevation of intraocular pressure in glaucomatous animal models and to cause retinal ganglion cell death, the discovery of a paravascular clearance system in the eye may provide powerful new insights into the pathophysiology of primary open‐angle glaucoma. In this review, we provide a new conceptual framework for understanding the pathogenesis of primary open‐angle glaucoma, present supporting preliminary data from our own post‐mortem study and hypothesize that the disease may result from restriction of normal glymphatic flow at the level of the lamina cribrosa owing to a low intracranial pressure and/or a high trans‐lamina cribrosa pressure gradient. If confirmed, this viewpoint could offer new perspectives for the development of novel diagnostic and therapeutic strategies for this devastating disorder.