A new glaucoma hypothesis: a role of glymphatic system dysfunction

Abstract

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.

Glaucoma: the retina and beyond

“…This hypothesis is contested on grounds including that the rigid structure of the lamina cribrosa will resist bowing at TLPDs of clinically relevant magnitude [74]. A second mechanism is that the dysregulation of CSF hydrodynamics, manifesting as elevated CSFP and resulting in accumulation of toxic compounds at the site of the ONH, leads to RGC loss [189]. There has been a recent resurgence in interest in the role of CSF turnover in CNS disorders with the re-discovery of the paravascular pathway for CSF and interstitial fluid exchange in the brain, termed the glymphatic system [82].…”

“…Dysregulation of glymphatic mediated clearance of interstitial solutes, including Aβ and Tau, has been suggested as a novel mechanism to explain the increased risk of dementia in patients after traumatic brain injury [80]. The dysregulation of the production and clearance of cytotoxic compounds, such as Aβ, coupled with recent postulations as to the existence of an ocular glymphatic system [40], has led to the development of a novel hypothesis for glaucoma pathology based on the reduction in CSF clearance from the SAS via ocular glymphatic dysregulation [189]. Therapeutic interventions to increase glymphatic clearance such as aquaporins agonists, which are currently under investigation for the treatment of AD, may also be of interest for the treatment of glaucoma [174].…”

Early changes of brain connectivity in primary open angle glaucoma

“…Importantly, we showed progressive hippocampal volume decrease through the POAG stages, until reaching an atrophic condition in the severe stage. Other features shared by POAG and AD are the molecular mechanisms of oxidative/metabolic stress, the loss of specific neuronal populations, glial reactivity [Ghiso et al, 2013], a high rate of POAG occurrence in Alzheimer patients [Bayer et al, 2002] and, more recently, a dysfunction of the "glymphatic" system, a brain-wide paravascular pathway that facilitates clearance of solutes, including amyloid-b, from the brain [Wostyn, et al, 2015]. It is conceivable that such mechanisms, hypothesized for typical neurodegenerative conditions [Hardy and Revesz, 2012], might also occur in the POAG brain and indeed abnormal accumulation of misfolded protein aggregates was reported in the visual system of (both experimental and human) glaucoma and Alzheimer disease [Gupta and Yucel, 2007;Jindal, 2013].…”

Significance of Understanding Function of Glymphatic System to Manage Practical Clinical Problems of the Elderly

“…Wostyn et al considering the structure of the glymphatic system inferred that observation of the function of this system in patients with glaucoma would probably provide support for their hypothesis that CSF circulatory dysfunction may contribute to the pathogenesis of glaucomatous damage [27]. Just like Alzheimer's disease, glaucoma might be caused by an imbalance between the production and clearance of neurotoxins, including amyloid-β [24].…”