Targeting the Cerebrospinal Fluid Compartment in Glaucoma: Still the Dark Side of the Moon? Comment on Passaro et al. Glaucoma as a Tauopathy-Is It the Missing Piece in the Glaucoma Puzzle? J. Clin. Med. 2023, 12, 6900.

I read with great interest the article by Passaro et al [...].

Could Young Cerebrospinal Fluid Combat Glaucoma? Comment on Lee et al. Association between Optic Nerve Sheath Diameter and Lamina Cribrosa Morphology in Normal-Tension Glaucoma. J. Clin. Med. 2023, 12, 360.

I enjoyed reading the article by Lee et al. [...].

Normal-Tension Glaucoma: A Glymphopathy?

Glaucoma is one of the main causes of irreversible blindness in the world. The most common form, primary open-angle glaucoma, is an optic neuropathy that is characterized by a progressive loss of retinal ganglion cells and their axons, leading to structural changes in the optic nerve head and associated visual field defects. Elevated intraocular pressure remains the most important modifiable risk factor for primary open-angle glaucoma. However, a significant proportion of patients develop glaucomatous damage in the absence of increased intraocular pressure, a condition known as normal-tension glaucoma (NTG). The pathophysiology underlying NTG remains unclear. Several studies have revealed that vascular and cerebrospinal fluid (CSF) factors may play significant roles in the development of NTG. Vascular failure caused by functional or structural abnormalities, and compartmentation of the optic nerve subarachnoid space with disturbed CSF dynamics have been shown to be associated with NTG. In the present article, based on the concept of the glymphatic system and observations in patients with NTG, we hypothesize that failure of fluid transport via the glymphatic pathway in the optic nerve may be involved in the pathogenesis of some if not many cases of NTG. According to this hypothesis, vascular and CSF factors may share reduced glymphatic transport and perivascular waste clearance in the optic nerve as a final common pathway leading to the development of NTG. In addition, we speculate that some cases of NTG may reflect glymphatic dysfunction in natural brain aging and central nervous system diseases, such as Alzheimer's disease. Clearly, further studies are needed to gain additional insight into the relative contribution of these factors and conditions to reduced glymphatic transport in the optic nerve.

Can Immersive Sound Therapy Counteract Neurodegeneration by Enhancing Glymphatic Clearance? Comment on Sachdeva et al. Effects of Sound Interventions on the Permeability of the Blood-Brain Barrier and Meningeal Lymphatic Clearance. Brain Sci. 2022, 12, 742.

We would like to congratulate Sachdeva and colleagues for establishing an informative review regarding the effects of music/sound exposure on blood-brain barrier permeability and meningeal lymphatic/glymphatic clearance, and would appreciate the opportunity to make a comment. The review by Sachdeva and colleagues documents the beneficial effects of sound interventions on blood-brain barrier permeability and the activity of the meningeal lymphatic/glymphatic system. The authors further note that sound interventions may have the potential to reduce the accumulation of amyloid-ß within the brain in Alzheimer's disease through improved meningeal lymphatic/glymphatic clearance. The authors also nicely discuss evidence that music influences sleep quality, which may facilitate glymphatic solute clearance as a result of an increase in the interstitial space, which results in reduced resistance to fluid transport. We fully agree with this notion, since we recently hypothesized that immersive sound therapy may be an innovative approach to reduce the individual risk of developing neurodegenerative diseases, such as Alzheimer's disease, by inducing EEG slow-wave delta oscillations (which characterize deep sleep), thereby promoting glymphatic clearance.

Does Long-Duration Exposure to Microgravity Lead to Dysregulation of the Brain and Ocular Glymphatic Systems?

Spaceflight-associated neuro-ocular syndrome (SANS) has been well documented in astronauts both during and after long-duration spaceflight and is characterized by the development of optic disc edema, globe flattening, choroidal folds, and hyperopic refractive error shifts. The exact mechanisms underlying these ophthalmic abnormalities remain unclear. New findings regarding spaceflight-associated alterations in cerebrospinal fluid spaces, specifically perivascular spaces, may shed more light on the pathophysiology of SANS. The preliminary results of a recent brain magnetic resonance imaging study show that perivascular spaces enlarge under prolonged microgravity conditions, and that the amount of fluid in perivascular spaces is linked to SANS. The exact pathophysiological mechanisms underlying enlargement of perivascular spaces in space crews are currently unclear. Here, we speculate that the dilation of perivascular spaces observed in long-duration space travelers may result from impaired cerebral venous outflow and compromised cerebrospinal fluid resorption, leading to obstruction of glymphatic perivenous outflow and increased periarterial cerebrospinal fluid inflow, respectively. Further, we provide a possible explanation for how dilated perivascular spaces can be associated with SANS. Given that enlarged perivascular spaces in space crews may be a marker of altered venous hemodynamics and reduced cerebrospinal fluid outflow, at the level of the optic nerve and eye, these disturbances may contribute to SANS. If confirmed by further studies, brain glymphatic dysfunction in space crews could potentially be considered a risk factor for the development of neurodegenerative diseases, such as Alzheimer's disease. Furthermore, long-duration exposure to microgravity might contribute to SANS through dysregulation of the ocular glymphatic system. If prolonged spaceflight exposure causes disruption of the glymphatic systems, this might affect the ability to conduct future exploration missions, for example, to Mars. The considerations outlined in the present paper further stress the crucial need to develop effective long-term countermeasures to mitigate SANS-related physiologic changes during long-duration spaceflight.

Optic Disc Edema in Astronauts from a Choroidal Point of View.

INTRODUCTION: Optic disc edema has been well documented in astronauts both during and after long-duration spaceflight and is hypothesized to largely result from increased pressure within the orbital subarachnoid space brought about by a generalized rise in intracranial pressure or from sequestration of cerebrospinal fluid within the orbital subarachnoid space with locally elevated optic nerve sheath pressure. In addition, a recent prospective study documented substantial spaceflight-associated peripapillary choroidal thickening, which may be a contributing factor in spaceflight-associated neuro-ocular syndrome. In the present article, based on the above, we offer a new perspective on the pathogenesis of microgravity-induced optic disc edema from a choroidal point of view. We propose that prolonged microgravity exposure may result in the transudation of fluid from the choroidal vasculature, which, in turn, may reach the optic nerve head, and ultimately may lead to fluid stasis within the prelaminar region secondary to impaired ocular glymphatic outflow. If confirmed, this viewpoint would shed new light on the development of optic disc edema in astronauts.Wostyn P, Gibson CR, Mader TH. Optic disc edema in astronauts from a choroidal point of view. Aerosp Med Hum Perform. 2022; 93(4):396-398.

The odyssey of the ocular and cerebrospinal fluids during a mission to Mars: the "ocular glymphatic system" under pressure.

A significant proportion of the astronauts who spend extended periods in microgravity develop ophthalmic abnormalities including optic disc edema, globe flattening, chorioretinal folds, and hyperopic refractive error shifts. A constellation of these neuro-ophthalmic findings has been termed "spaceflight-associated neuro-ocular syndrome". Understanding this syndrome is currently a top priority for NASA, especially in view of future long-duration missions (e.g., Mars missions). The recent discovery of an "ocular glymphatic system" can potentially help to unlock mechanisms underlying microgravity-induced optic disc edema. Indeed, a major paradigm shift is currently occurring in our understanding of transport of fluids and solutes through the optic nerve following the recent discovery of an optic nerve glymphatic pathway for influx of cerebrospinal fluid. In addition, the recent identification of an entirely new glymphatic pathway for efflux of ocular fluid may have profound implications for fluid dynamics in the eye. Observations pertaining to this ocular glymphatic pathway provide critical new insights into how intracranial pressure can alter basic fluid transport in the eye. We believe that these novel findings have the potential to be game changers in our understanding of the pathogenesis of optic disc edema in astronauts. In the present review, we integrate these new insights with findings on the intracranial and neuro-ophthalmologic effects of microgravity in one coherent conceptual framework. Further studies in this area of investigation could not only provide exciting new insights into the mechanisms underlying microgravity-induced optic disc edema but also offer opportunities to develop countermeasure strategies.