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

Abstract

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.

Keywords: astronaut; cerebrospinal fluid; glymphatic system; optic disc edema; perivascular spaces; spaceflight-associated neuro-ocular syndrome.

Figure 1

The brain and ocular glymphatic systems. Macroscopic overview of the brain and ocular glymphatic systems, emphasizing the role played by pressure gradients, hydrostatic barriers, and lymphatic drainage, shown in the context of known pathways for aqueous humour and cerebrospinal fluid (CSF) efflux. ICP, intracranial pressure; IOP, intraocular pressure. Figure reproduced from Rangroo Thrane V, Hynnekleiv L, Wang X, Thrane AS, Krohn J, Nedergaard M. Twists and turns of ocular glymphatic clearance – new study reveals surprising findings in glaucoma. Acta Ophthalmol. 2021;99(2):e283–e284..

Figure 2

Proposed mechanisms underlying dilated perivascular spaces in space crews in relation to spaceflight-associated neuro-ocular syndrome. (A) Blood volume in cerebral veins may increase as a result of a microgravity-induced decrease in cerebral venous outflow, which in turn, may lead to closure of the perivenous spaces, thereby compromising the glymphatic CSF-ISF outflow from the interstitial tissue, and resulting in diminished glymphatic clearance of metabolites from the brain. Consequently, periarterial spaces may dilate due to CSF accumulation. A reduced CSF resorption and mildly elevated ICP in microgravity may further drive CSF into the periarterial spaces, causing further fluid accumulation and PVS dilation. (B) If the cephalad venous fluid shift during spaceflight is associated with increased resistance to venous drainage from the eye, veins in the optic nerve may distend and perivenous spaces may close, resulting in diminished ocular glymphatic outflow. (C) Compromised CSF resorption and impaired cerebral venous outflow, reflected by dilated PVS, may contribute to globe flattening and optic disc edema through overflow of CSF along the optic nerve sheath and dysregulation of the ocular glymphatic system, respectively.