Sleep deprivation and glymphatic system dysfunction as a risk factor for SANS during long-duration spaceflight.

During long-duration spaceflights, nearly all astronauts exhibit some change in ocular structure within the spectrum of spaceflight-associated neuro-ocular syndrome. To quantitatively determine in a prospective study whether changes in ocular structures hypothesized to be associated with the development of spaceflight-associated neuro-ocular syndrome occur during 6-month missions on board the International Space Station (ISS). The Ocular Health ISS Study of astronauts is a longitudinal prospective cohort study that uses objective quantitative imaging modalities. The present cohort study investigated the ocular structure of 11 astronauts before, during, and after a 6-month mission on board the ISS. Changes in ocular structure (peripapillary edema, axial length, anterior chamber depth, and refraction) hypothesized to be associated with the development of spaceflight-associated neuro-ocular syndrome during 6-month missions on board the ISS were assessed. Statistical analyses were conducted from August 2018 to January 2019. Before launch, the 11 astronauts were a mean (SD) age of 45 (5) years, a mean (SD) height of 1.76 (0.05) m, and a mean (SD) weight of 75.3 (7.1) kg. Six astronauts did not have prior spaceflight experience, 3 had completed short-duration missions on board the Space Shuttle, and 2 had previous long-duration spaceflight missions on board the ISS. Their mean (SD) duration on board the ISS in the present study was 170 (19) days. Optic nerve head rim tissue and peripapillary choroidal thickness increased from preflight values during early spaceflight, with maximal change typically near the end of the mission (mean change in optic nerve head rim tissue thickness on flight day 150: 35.7 μm; 95% CI, 28.5-42.9 μm; P < .001; mean choroidal thickness change on flight day 150: 43 μm; 95% CI, 35-46 μm; P < .001). The mean postflight axial length of the eye decreased by 0.08 mm (95% CI, 0.10-0.07 mm; P < .001) compared with preflight measures, and this change persisted through the last examination (1 year after spaceflight: 0.05 mm; 95% CI, 0.07-0.03 mm; P < .001). This study found that spaceflight-associated peripapillary optic disc edema and choroid thickening were observed bilaterally and occurred in both sexes. In addition, this study documented substantial peripapillary choroid thickening during spaceflight, which has never been reported in a prospective study cohort population and which may be a contributing factor in spaceflight-associated neuro-ocular syndrome. Data collection on spaceflight missions longer than 6 months will help determine whether the duration of the mission is associated with exacerbating these observed changes in ocular structure or visual function.

Spaceflight associated neuro-ocular syndrome (SANS) alters the vision of astronauts during long-duration spaceflights. There is controversy regarding SANS being similar to patients with idiopathic intracranial hypertension (IIH). IIH has been shown to be due to an elevation in venous sinus pressure. The literature suggests an increase in jugular vein pressure secondary to a headward shift of fluid occurs in SANS but this may not be enough to significantly alter the intracranial pressure (ICP). The literature regarding cardiac output and cerebral blood flow (CBF) in long-duration spaceflight is contradictory, however, more recent data suggests increased flow. Recent modelling has shown that an increase in CBF can significantly increase sinus pressure. The purpose of the present paper is to review the SANS vascular dynamics literature and through mathematical modelling suggest the possible underlying cause of SANS as an elevation in venous sinus pressure, secondary to the redistribution of fluids towards the head, together with a significant increase in pressure drop across the venous system related to the CBF.

Interesting novel and somewhat perplexing physiologic and pathologic neuro-ocular findings have been documented in astronauts during and after long duration space flight (LDSF). These findings collectively have been termed the "space flight-associated neuro-ocular syndrome" (SANS). The National Aeronautics and Space Administration (NASA) in the United States has meticulously and prospectively documented the clinical, ultrasound, optical coherence tomography imaging, and radiographic findings of SANS including unilateral and bilateral optic disc edema, globe flattening, choroidal and retinal folds, hyperopic refractive error shifts, and nerve fiber layer infarcts (i.e., cotton wool spots). NASA and collaborating researchers continue to study SANS in preparation for future manned missions to space, including continued trips to the ISS, a return to the moon, or perhaps new voyages to the asteroid belt, or the planet, Mars.

PurposeTo present a systematic review of the current body of literature surrounding spaceflight associated neuro-ocular syndrome (SANS) and highlight priorities for future research.MethodsThree major biomedical databases were searched with the following terms: ((neuro ocular) OR ((brain) AND (eye))) AND ((spaceflight) OR (astronaut) OR (microgravity)) AND (ENGLISH[Language]). Once duplicates were removed, 283 papers were left. Articles were excluded if they were not written in English or conference abstracts only. We avoided including review papers which did not provide any new information; however, two reviews on the pathophysiology of SANS were included for completeness. No limitations on date of publication were used. All included entries were then summarized for their contribution to knowledge about SANS.ResultsFour main themes among the publications emerged: papers defining the clinical entity of SANS, its pathophysiology, technology used to study SANS, and publications on possible prevention of SANS. The key clinical features of SANS include optic nerve head elevation, hyperopic shifts, globe flattening, choroidal folds, and increased cerebrospinal fluid (CSF) volume in optic nerve sheaths. Two main hypotheses are proposed for the pathophysiology of SANS. The first being elevated intracranial pressure and the second compartmentalization of CSF to the globe. These hypotheses are not mutually exclusive, and our understanding of the pathophysiology of SANS is still evolving. The use of optical coherence tomography (OCT) has greatly furthered our knowledge about SANS, and with the deployment of OCT to the International Space Station, we now have ability to collect intraflight data. No effective prevention for SANS has been found, although fortunately, even with persistent anatomic and physiologic neuro-ocular changes, any functional impact has been correctable with spectacles.ConclusionThis is the first systematic review of SANS. Despite the limitations of studying a syndrome that can only occur in a small, discrete population, we present a thorough overview of the literature surrounding SANS and several key areas important for future research are identified.

Spaceflight associated neuro-ocular syndrome (SANS) is one of the potential barriers to human long-duration spaceflight (LDSF), including a manned mission to Mars. While a large barrier, the pathophysiology of SANS is not well understood, and functional and structural findings from SANS continue to be further characterized. Currently on the International Space Station (ISS), scheduled visual assessments are static visual acuity, Amsler grid, and a self-reported survey. Additional visual assessments may help the understanding of this neuro-ophthalmic phenomenon, as well as the effects of spaceflight of overall ocular health. In this paper, a case is made for expanding scheduled visual assessments to include dynamic visual, contrast sensitivity (CS), visual field testing, and virtual reality-based metamorphopsia assessment during spaceflight. These further assessments may play a key role in helping to determine the structural and functional changes associated with SANS, which are crucial to maintain astronaut vision during LDSF, as well as for developing countermeasures. Finally, a brief discussion is provided about current challenges to expanding visual testing during spaceflight and potential solutions to these barriers, specifically head-mounted visual assessment technology.

Re: Stenger et al.: Focus on the optic nerve head in spaceflight-associated neuro-ocular syndrome (Ophthalmology. 2019;126:1604–1606)

BackgroundWith beta amyloid and tau antibody treatment trial failures, avenues directed to other aspects of the disease pathophysiology are being explored to treat in the preclinical or early clinical state. Clear evidence of blood brain barrier (BBB) breakdown occurring early in the AD process has recently been established. Likewise, the glymphatic system regulating water and solute inflow and outflow in parallel with the vascular system is affected causing delayed clearance of fluid waste. Its dysfunction as a component of AD along with BBB leak are reasonable candidates to explore for future treatments.MethodWe will review the known physiology and anatomy of the BBB system, its relationship to the glymphatic system and the microglial surveillance system. Ideally, human medication trials require a non or minimally invasive method of quantifying both improvements in BBB integrity and glymphatic fluid clearance correlated with clinical outcomes.ResultDysfunction of this tripart system occurring in Alzheimer disease (AD) will be reviewed along with existing MRI tools for identifying altered flow dynamics useful for monitoring improved functionality with future treatments.ConclusionHigh resolution dynamic contrast enhanced MRI imaging demonstrating BBB leak and the recently reported non‐invasive 3D PASL MRI pilot study demonstrating significant delay in glymphatic clearance in AD subjects appear to be the best candidates.

Jumping at a chance to control cerebral blood flow in astronauts.

Alzheimer’s disease (AD) is the leading cause of dementia worldwide. The disease is characterized by the abnormal accumulation of amyloid β (Aβ) protein creating neuritic plaques, hyperphosphorylated tau (p-tau) protein forming intracellular tangles, and neuronal degeneration. Pathological changes related to abnormal Aβ and p-tau accumulation may begin more than fifteen years before the clinical diagnosis of AD is made. The glymphatic system is the brain’s waste clearance pathway that prevents the accumulation of these abnormal proteins and macromolecules. Glymphatic clearance is negatively affected by physiological conditions such as sleep deprivation, and pathological conditions such as traumatic brain injury and hemorrhagic strokes. These physiological and pathological conditions are strong risk factors for AD. In conclusion, impaired glymphatic clearance is an important pathogenetic mechanism for AD.

Alzheimer’s disease (AD) is the most common cause of neurodegenerative dementia, whilst Parkinson’s disease (PD) is a neurodegenerative movement disorder. These two neurodegenerative disorders share the accumulation of toxic proteins as a pathological hallmark. The lack of definitive disease-modifying treatments for these neurogenerative diseases has led to the hypothesis of new pathogenic mechanisms to target and design new potential therapeutic approaches. The recent observation that the glymphatic system is supposed to be responsible for the movement of cerebrospinal fluid into the brain and clearance of metabolic waste has led to study its involvement in the pathogenesis of these classic proteinopathies. Aquaporin-4 (AQP4), a water channel located in the endfeet of astrocyte membrane, is considered a primary driver of the glymphatic clearance system, and defective AQP4-mediated glymphatic drainage has been linked to proteinopathies. The objective of the present review is to present the recent body of knowledge that links the glymphatic system to the pathogenesis of AD and PD disease and other lifestyle factors such as sleep deprivation and exercise that may influence glymphatic system function. We will also focus on the potential neuroimaging approaches that could identify a neuroimaging marker to detect glymphatic system changes.

Continuous theta burst stimulation facilitates the clearance efficiency of the glymphatic pathway in a mouse model of sleep deprivation.

O.066 VEGF/VEGFR-2 changes in brain, CSF and choroid plexus after chronic obstructive hydrocephalus

The etiology of spaceflight-associated neuro-ocular syndrome (SANS) is a developing field of research, with many current hypotheses receiving varying degrees of support. This syndrome affects ∼70% of astronauts both during and after long-duration space missions, resulting in impaired near vision and visual scotomas (blind spots). In this article, three prominent risk factors for SANS including zero gravity conditions, extraterrestrial hypercapnic environments, and individual genetic predisposition are described. These risk factors are then compared and their pathophysiological pathways are divided into five current hypotheses for the development of SANS. Finally, glymphatic system impairment is explored as a potential mutual end point for these pathways in the development of SANS.

OBJECTIVETo determine whether the combination of a cephalad fluid shift induced by headdown tilt (HDT) bed rest and chronic exposure to mild hypercapnia for 30 days will alter sleep architecture and circadian rhythm, contributing to characteristics of Spaceflight Associated Neuro‐ocular Syndrome (SANS).METHODSAfter 14 days of ambulatory normocapnic familiarization with the facility and baseline data collection (BDC), eleven subjects (5 female) breathed mild, ambient hypercapnia (0.5% CO2) throughout 30 days of 6° HDT at the German Aerospace Center (DLR): envihab facility. Following HDT, subjects were monitored for an additional 14 days of ambulatory, normocapnic recovery (R). Overnight polysomnography (PSG) was measured using a type‐2 sleep monitoring system, and the PSG was scored by a Polysomnographic Technologist to assess sleep duration, staging, latency, and arousals. Circadian rhythm was assessed by monitoring 24‐hour core body temperature with rectal temperature probes. Arterial PCO2 levels were estimated from transcutaneous PCO2 monitoring throughout sleep. Retinal thickness was measured via optical coherence tomography (OCT); those with increased thickness &gt;50μ in the nasal quadrant were classified as RET+, those &lt;50μ were classified as RET‐. After one night of familiarization with the instrumentation, measurements were collected at six different time points (one BDC, three HDT, and two R).RESULTSWhen comparing RET+ to RET‐, subjects had: significantly less total sleep time (TST) in BDC (345 ± 25 min vs 401 ± 23 min, p &lt; 0.05), HDT4 (303 ± 64 min vs 375 ± 20 min, p &lt; 0.05), HDT28 (344 ± 59 min vs 407 ± 32 min, p &lt; 0.05), and R+4 (344 ± 68 min vs 421 ± 21 min, p &lt; 0.05); significantly less stage 2 (N2) sleep in HDT4 (157 ± 43 min vs 220 ± 9 min, p &lt; 0.05), HDT28 (198 ± 32 min vs 256 ± 21 min, p &lt; 0.05), and R+4 (187 ± 74 min vs 271 ± 32, p &lt; 0.05); significantly more wake after sleep onset (WASO) in HDT4 (147 ± 85 min vs 57 ± 27 min, p &lt; 0.05) and R+4 (134 ± 106 min vs 41 ± 12 min, p &lt; 0.05); and a significantly reduced core body temperature amplitude at BDC (0.3 ± 0.1 deg vs 0.5 ± 0.1 deg, p &lt; 0.05), HDT4 (0.2 ± 0.1 deg vs 0.4 ± 0.1 deg, p &lt; 0.05), HDT28 (0.3 ± 0.1 deg vs 0.4 ± 0.1 deg, p &lt; 0.05), and R+10 (0.3 ± 0.0 deg vs 0.4 ± 0.1 deg, p &lt; 0.05).CONCLUSIONSPrior to and throughout the experimental conditions, when compared to RET‐, RET+ subjects were “short” sleepers and in general had less N2 sleep, greater WASO, and had a lower amplitude of core body temperature. We conclude that insufficient sleep may predispose certain individuals to the development of retinal thickening, a finding of SANS. Objective PSG may be a potential variable to consider when determining astronaut spaceflight duration.Support or Funding InformationNASA Human Research Program NNJ14ZSA001NThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

There is growing evidence pointing at glymphatic system dysfunction in diseases with circadian disruption, such as sleep disorders. Lower diffusivity in the direction of perivascular space has been shown in several neurological and sleep-related disorders; however, its role in restless legs syndrome (RLS) is unclear. We hypothesized that similarly, in RLS the diffusivity in glymphatic system is decreased. Here, we aimed to evaluate glymphatic system functionality in patients with RLS, compare it to healthy controls, and analyze the correlation between its function and clinical characteristics. Sixty-nine patients with primary RLS and 51 healthy controls were recruited at a tertiary hospital. All participants underwent diffusion tensor imaging (DTI) and magnetic resonance imaging (MRI) using a 3T MRI scanner, and the DTI along the perivascular space (DTI-ALPS) index was calculated using DTI data. We compared the DTI-ALPS index between the patients with RLS and healthy controls. We also conducted the correlation analysis between the DTI-ALPS index and clinical characteristics, including age, age of onset, symptom duration, and RLS severity. DTI-ALPS index differed significantly between the patients with RLS and healthy controls; the DTI-ALPS index in the patients with RLS was lower than that in the healthy controls (1.48 vs. 0.60, p = 0.008). There was no significant correlation between the DTI-ALPS index and clinical characteristics. A significantly lower DTI-ALPS index in patients with RLS suggests that the glymphatic system function is impaired in patients with RLS.