The Ocular Glymphatic System-Current Understanding and Future Perspectives.

The ocular glymphatic system subserves the bidirectional polarized fluid transport in the optic nerve, whereby cerebrospinal fluid from the brain is directed along periarterial spaces towards the eye, and fluid from the retina is directed along perivenous spaces following upon its axonal transport across the glial lamina. Fluid homeostasis and waste removal are vital for retinal function, making the ocular glymphatic fluid pathway a potential route for targeted manipulation to combat blinding ocular diseases such as age-related macular degeneration, diabetic retinopathy, and glaucoma. Several lines of work investigating the bidirectional ocular glymphatic transport with varying methodologies have developed diverging mechanistic models, which has created some confusion about how ocular glymphatic transport should be defined. In this review, we provide a comprehensive summary of the current understanding of the ocular glymphatic system, aiming to address misconceptions and foster a cohesive understanding of the topic.

Glymphatic pathway: An emerging perspective in the pathophysiology of neurodegenerative diseases.

The central nervous system (CNS) is widely recognized as the only organ system without lymphatic capillaries to promote the removal of interstitial metabolic by-products. Thus, the newly identified glymphatic system which provides a pseudolymphatic activity in the nervous system has been focus of latest research in neurosciences. Also, findings reported that, sleep stimulates the elimination actions of glymphatic system and is linked to normal brain homeostatis. The CNS is cleared of potentially hazardous compounds via the glymphatic system, particularly during sleep. Any age-related alterations in brain functioning and pathophysiology of various neurodegenerative illnesses indicates the disturbance of the brain's glymphatic system. In this context, ß-amyloid as well as tau leaves the CNS through the glymphatic system, it's functioning and CSF discharge markedly altered in elderly brains as per many findings. Thus, glymphatic failure may have a potential mechanism which may be therapeutically targetable in several neurodegenerative and age-associated cognitive diseases. Therefore, there is an urge to focus for more research into the connection among glymphatic system and several potential brain related diseases. Here, in our current review paper, we reviewed current research on the glymphatic system's involvement in a number of prevalent neurodegenerative and neuropsychiatric diseases and, we also discussed several therapeutic approaches, diet and life style modifications which might be used to acquire a more thorough performance and purpose of the glymphatic system to decipher novel prospects for clinical applicability for the management of these diseases.

Advances in the study of the glymphatic system and aging.

The glymphatic system is cerebrospinal fluid-brain tissue fluid exchange flow mediated by aquaporin-4 (AQP4) on the end feet of astrocytes for a system, which is capable of rapidly removing brain metabolites and thus maintaining brain homeostasis, and is known as the central immune system. Dysfunction of the glymphatic system causes accumulation of misfolded and highly phosphorylated proteins (amyloid-ß and Tau proteins), which destabilizes the proteins, and the body's neuroinflammatory factors are altered causing aging of the immune system and leading to neurodegenerative diseases. Damage to the glymphatic system and aging share common manifestations, as well as unstudied biological mechanisms that are also linked, such as mitochondria, oxidative stress, chronic inflammation, and sleep. In this paper, we first summarize the structure, function, and research methods of the glymphatic system and the relationship between the glymphatic system and the peripheral immune system, and second, sort out and summarize the factors of the glymphatic system in removing metabolites and resolving aging-related diseases and factors affecting aging, to explore its related biological mechanisms, and moreover, to provide a new way of thinking for treating or intervening aging-related diseases.

Neurosurgery and the glymphatic system.

The discovery of the glymphatic system has fundamentally altered our comprehension of cerebrospinal fluid transport and the removal of waste from brain metabolism. In the past decade, since its initial characterization, research on the glymphatic system has surged exponentially. Its potential implications for central nervous system disorders have sparked significant interest in the field of neurosurgery. Nonetheless, ongoing discussions and debates persist regarding the concept of the glymphatic system, and our current understanding largely relies on findings from experimental animal studies. This review aims to address several key inquiries: What methodologies exist for evaluating glymphatic function in humans today? What is the current evidence supporting the existence of a human glymphatic system? Can the glymphatic system be considered distinct from the meningeal-lymphatic system? What is the human evidence for glymphatic-meningeal lymphatic system failure in neurosurgical diseases? Existing literature indicates a paucity of techniques available for assessing glymphatic function in humans. Thus far, intrathecal contrast-enhanced magnetic resonance imaging (MRI) has shown the most promising results and have provided evidence for the presence of a glymphatic system in humans, albeit with limitations. It is, however, essential to recognize the interconnection between the glymphatic and meningeal lymphatic systems, as they operate in tandem. There are some human studies demonstrating deteriorations in glymphatic function associated with neurosurgical disorders, enriching our understanding of their pathophysiology. However, the translation of this knowledge into clinical practice is hindered by the constraints of current glymphatic imaging modalities.

Arterial pulsation dependence of perivascular cerebrospinal fluid flow measured by dynamic diffusion tensor imaging in the human brain.

Perivascular cerebrospinal fluid (pCSF) flow is a key component of the glymphatic system. Arterial pulsation has been proposed as the main driving force of pCSF influx along the superficial and penetrating arteries; however, evidence of this mechanism in humans is limited. We proposed an experimental framework of dynamic diffusion tensor imaging with low b-values and ultra-long echo time (dynDTIlow-b) to capture pCSF flow properties during the cardiac cycle in human brains. Healthy adult volunteers (aged 17-28 years; seven men, one woman) underwent dynDTIlow-b using a 3T scanner (MAGNETOM Prisma, Siemens Healthcare, Erlangen, Germany) with simultaneously recorded cardiac output. The results showed that diffusion tensors reconstructed from pCSF were mainly oriented in the direction of the neighboring arterial flow. When switching from vasoconstriction to vasodilation, the axial and radial diffusivities of the pCSF increased by 5.7 % and 4.94 %, respectively, suggesting that arterial pulsation alters the pCSF flow both parallel and perpendicular to the arterial wall. DynDTIlow-b signal intensity at b=0 s/mm2 (i.e., T2-weighted, [S(b=0 s/mm2)]) decreased in systole, but this change was ∼7.5 % of a cardiac cycle slower than the changes in apparent diffusivity, suggesting that changes in S(b=0 s/mm2) and apparent diffusivity arise from distinct physiological processes and potential biomarkers associated with perivascular space volume and pCSF flow, respectively. Additionally, the mean diffusivities of white matter showed cardiac-cycle dependencies similar to pCSF, although a delay relative to the peak time of apparent diffusivity in pCSF was present, suggesting that dynDTIlow-b could potentially reveal the dynamics of magnetic resonance imaging-invisible pCSF surrounding small arteries and arterioles in white matter; this delay may result from pulse wave propagation along penetrating arteries. In conclusion, the vasodilation-induced increases in axial and radial diffusivities of pCSF and mean diffusivities of white matter are consistent with the notion that arterial pulsation can accelerate pCSF flow in human brain. Furthermore, the proposed dynDTIlow-b technique can capture various pCSF dynamics in artery pulsation.

Transcranial direct current stimulation alters cerebrospinal fluid-interstitial fluid exchange in mouse brain.

BACKGROUND: Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that has gained prominence recently. Clinical studies have explored tDCS as an adjunct to neurologic disease rehabilitation, with evidence suggesting its potential in modulating brain clearance mechanisms. The glymphatic system, a proposed brain waste clearance system, posits that cerebrospinal fluid-interstitial fluid (CSF-ISF) exchange aids in efficient metabolic waste removal. While some studies have linked tDCS to astrocytic inositol trisphosphate (IP3)/Ca2+ signaling, the impact of tDCS on CSF-ISF exchange dynamics remains unclear. HYPOTHESIS: tDCS influences the dynamics of CSF-ISF exchange through astrocytic IP3/Ca2+ signaling. METHODS: In this study, we administered tDCS (0.1 mA for 10 min) to C57BL/6N mice anesthetized with ketamine-xylazine (KX). The anode was positioned on the cranial bone above the cortex, and the cathode was inserted into the neck. Following tDCS, we directly assessed brain fluid dynamics by injecting biotinylated dextran amine (BDA) as a CSF tracer into the cisterna magna (CM). The brain was then extracted after either 30 or 60 min and fixed. After 24 h, the sectioned brain slices were stained with Alexa 594-conjugated streptavidin (SA) to visualize BDA using immunohistochemistry. We conducted Electroencephalography (EEG) recordings and aquaporin 4 (AQP4)/CD31 immunostaining to investigate the underlying mechanisms of tDCS. Additionally, we monitored the efflux of Evans blue, injected into the cisterna magna, using cervical lymph node imaging. Some experiments were subsequently repeated with inositol trisphosphate receptor type 2 (IP3R2) knockout (KO) mice. RESULTS: Post-tDCS, we observed an increased CSF tracer influx, indicating a modulation of CSF-ISF exchange by tDCS. Additionally, tDCS appeared to enhance the brain's metabolic waste efflux. EEG recordings showed an increase in delta wave post-tDCS. But no significant change in AQP4 expression was detected 30 min post-tDCS. Besides, we found no alteration in CSF-ISF exchange and delta wave activity in IP3R2 KO mice after tDCS. CONCLUSION: Our findings suggest that tDCS augments the glymphatic system's influx and efflux. Through astrocytic IP3/Ca2+ signaling, tDCS was found to modify the delta wave, which correlates positively with brain clearance. This study underscores the potential of tDCS in modulating brain metabolic waste clearance.

Gaps in the wall of a perivascular space act as valves to produce a directed flow of cerebrospinal fluid: a hoop-stress model.

The flow of cerebrospinal fluid (CSF) along perivascular spaces (PVSs) is an important part of the brain's system for clearing metabolic waste. Astrocyte endfeet bound the PVSs of penetrating arteries, separating them from brain extracellular space. Gaps between astrocyte endfeet might provide a low-resistance pathway for fluid transport across the wall. Recent studies suggest that the astrocyte endfeet function as valves that rectify the CSF flow, producing the net flow observed in pial PVSs by changing the size of the gaps in response to pressure changes. In this study, we quantify this rectification based on three features of the PVSs: the quasi-circular geometry, the deformable endfoot wall, and the pressure oscillation inside. We provide an analytical model, based on the thin-shell hoop-stress approximation, and predict a pumping efficiency of about 0.4, which would contribute significantly to the observed flow. When we add the flow resistance of the extracellular space (ECS) to the model, we find an increased net flow during sleep, due to the known increase in ECS porosity (decreased flow resistance) compared to that in the awake state. We corroborate our analytical model with three-dimensional fluid-solid interaction simulations.

Multisensory gamma stimulation promotes glymphatic clearance of amyloid.

The glymphatic movement of fluid through the brain removes metabolic waste1-4. Noninvasive 40 Hz stimulation promotes 40 Hz neural activity in multiple brain regions and attenuates pathology in mouse models of Alzheimer's disease5-8. Here we show that multisensory gamma stimulation promotes the influx of cerebrospinal fluid and the efflux of interstitial fluid in the cortex of the 5XFAD mouse model of Alzheimer's disease. Influx of cerebrospinal fluid was associated with increased aquaporin-4 polarization along astrocytic endfeet and dilated meningeal lymphatic vessels. Inhibiting glymphatic clearance abolished the removal of amyloid by multisensory 40 Hz stimulation. Using chemogenetic manipulation and a genetically encoded sensor for neuropeptide signalling, we found that vasoactive intestinal peptide interneurons facilitate glymphatic clearance by regulating arterial pulsatility. Our findings establish novel mechanisms that recruit the glymphatic system to remove brain amyloid.

The glymphatic system and cerebral small vessel disease.

OBJECTIVES: Cerebral small vessel disease is a group of pathologies in which alterations of the brain's blood vessels contribute to stroke and neurocognitive changes. Recently, a neurotoxic waste clearance system composed of perivascular spaces abutting the brain's blood vessels, termed the glymphatic system, has been identified as a key player in brain homeostasis. Given that small vessel disease and the glymphatic system share anatomical structures, this review aims to reexamine small vessel disease in the context of the glymphatic system and highlight novel aspects of small vessel disease physiology. MATERIALS AND METHODS: This review was conducted with an emphasis on studies that examined aspects of small vessel disease and on works characterizing the glymphatic system. We searched PubMed for relevant articles using the following keywords: glymphatics, cerebral small vessel disease, arterial pulsatility, hypertension, blood-brain barrier, endothelial dysfunction, stroke, diabetes. RESULTS: Cerebral small vessel disease and glymphatic dysfunction are anatomically connected and significant risk factors are shared between the two. These include hypertension, type 2 diabetes, advanced age, poor sleep, obesity, and neuroinflammation. There is clear evidence that CSVD hinders the effective functioning of glymphatic system. CONCLUSION: These shared risk factors, as well as the model of cerebral amyloid angiopathy pathogenesis, hint at the possibility that glymphatic dysfunction could independently contribute to the pathogenesis of cerebral small vessel disease. However, the current evidence supports a model of cascading dysfunction, wherein concurrent small vessel and glymphatic injury hinder glymphatic-mediated recovery and promote the progression of subclinical to clinical disease.

The glymphatic system and multiple sclerosis: An evolving connection.

Multiple sclerosis (MS) is a complex autoimmune disorder that affects the central nervous system, resulting in demyelination and an array of neurological manifestations. Recently, there has been significant scientific interest in the glymphatic system, which operates as a waste-clearance system for the brain. This article reviews the existing literature, and explores potential links between the glymphatic system and MS, shedding light on its evolving significance in the context of MS pathogenesis. The authors consider the pathophysiological implications of glymphatic dysfunction in MS, the impact of disrupted sleep on glymphatic function, and the bidirectional relationship between MS and sleep disturbances. By offering an understanding of the intricate interplay between the glymphatic system and MS, this review provides valuable insights which may lead to improved diagnostic techniques and more effective therapeutic interventions.

Neurofluids and the glymphatic system: anatomy, physiology, and imaging.

First described in 2012, the glymphatic system is responsible for maintaining homeostasis within the central nervous system, including nutrient delivery, waste clearance, and consistency of the ionic microenvironment. It is comprised of glial cells and barrier systems that modulate neurofluid production, circulation, and exchange. Experimental interrogation of neurofluid dynamics is restricted to ex vivo and in vitro studies in animals and humans, therefore diagnostic imaging plays an important role in minimally invasive evaluation. This review article will synthesize current knowledge and theories regarding neurofluid circulation and implications for neuroimaging. First, we will discuss the anatomy of the neurogliovascular unit, including paravascular and perivascular pathways of fluid exchange. In addition, we will summarize the structure and function of barrier systems including the blood-brain, blood-cerebrospinal fluid, and brain-cerebrospinal fluid barriers. Next, we will mention physiologic factors that yield normal variations in neurofluid circulation, and how various disease pathologies can disrupt glymphatic drainage pathways. Lastly, we will cover the spectrum of diagnostic imaging and interventional techniques with relevance to glymphatic structure, flow, and function. We conclude by highlighting current barriers and future directions for translational imaging and applications to neurologic disorders.

Higher order diffusion imaging as a putative index of human sleep-related microstructural changes and glymphatic clearance.

The brain has a unique macroscopic waste clearance system, termed the glymphatic system which utilises perivascular tunnels surrounded by astroglia to promote cerebrospinal-interstitial fluid exchange. Rodent studies have demonstrated a marked increase in glymphatic clearance during sleep which has been linked to a sleep-induced expansion of the extracellular space and concomitant reduction in intracellular volume. However, despite being implicated in the pathophysiology of multiple human neurodegenerative disorders, non-invasive techniques for imaging glymphatic clearance in humans are currently limited. Here we acquired multi-shell diffusion weighted MRI (dwMRI) in twenty-one healthy young participants (6 female, 22.3 ± 3.2 years) each scanned twice, once during wakefulness and once during sleep induced by a combination of one night of sleep deprivation and 10 mg of the hypnotic zolpidem 30 min before scanning. To capture hypothesised sleep-associated changes in intra/extracellular space, dwMRI were analysed using higher order diffusion modelling with the prediction that sleep-associated increases in interstitial (extracellular) fluid volume would result in a decrease in diffusion kurtosis, particularly in areas associated with slow wave generation at the onset of sleep. In line with our hypothesis, we observed a global reduction in diffusion kurtosis (t15=2.82, p = 0.006) during sleep as well as regional reductions in brain areas associated with slow wave generation during early sleep and default mode network areas that are highly metabolically active during wakefulness. Analysis with a higher-order representation of diffusion (MAP-MRI) further indicated that changes within the intra/extracellular domain rather than membrane permeability likely underpin the observed sleep-associated decrease in kurtosis. These findings identify higher-order modelling of dwMRI as a potential new non-invasive method for imaging glymphatic clearance and extend rodent findings to suggest that sleep is also associated with an increase in interstitial fluid volume in humans.

Neuroinflammation with increased glymphatic flow in a murine model of decompression sickness.

This project investigated glial-based lymphatic (glymphatic) function and its role in a murine model of decompression sickness (DCS). DCS pathophysiology is traditionally viewed as being related to gas bubble formation from insoluble gas on decompression. However, a body of work implicates a role for a subset of inflammatory extracellular vesicles, 0.1 to 1 µm microparticles (MPs) that are elevated in human and rodent models in response to high gas pressure and rise further after decompression. Herein, we describe immunohistochemical and Western blot evidence showing that following high air pressure exposure, there are elevations of astrocyte NF-κB and microglial-ionized calcium-binding adaptor protein-1 (IBA-1) along with fluorescence contrast and MRI findings of an increase in glymphatic flow. Concomitant elevations of central nervous system-derived MPs coexpressing thrombospondin-1 (TSP) drain to deep cervical nodes and then to blood where they cause neutrophil activation. A new set of blood-borne MPs are generated that express filamentous actin at the surface that exacerbate neutrophil activation. Blood-brain barrier integrity is disrupted due to activated neutrophil sequestration that causes further astrocyte and microglial perturbation. When postdecompression node or blood MPs are injected into naïve mice, the same spectrum of abnormalities occur and they are blocked with coadministration of antibody to TSP. We conclude that high pressure/decompression causes neuroinflammation with an increased glymphatic flow. The resulting systemic liberation of TSP-expressing MPs sustains the neuroinflammatory cycle lasting for days.NEW & NOTEWORTHY A murine model of central nervous system (CNS) decompression sickness demonstrates that high gas pressure activates astrocytes and microglia triggering inflammatory microparticle (MP) production. Thrombospondin-expressing MPs are released from the CNS via enhanced glymphatic flow to the systemic circulation where they activate neutrophils. Secondary production of neutrophil-derived MPs causes further cell activation and neutrophil adherence to the brain microvasculature establishing a feed-forward neuroinflammatory cycle.

[The glymphatic system - an overview]. / Glymfatiska systemet ­ renar hjärnan från slaggprodukter.

The glymphatic system as a concept was introduced a decade ago and the knowledge regarding the circulation of the cerebrospinal fluid has since been revised. The research of the glymphatic system is extensive today, but there are many knowledge gaps. The glymphatic system was first investigated in animal experiments, but with the MR techniques available today the glymphatic system has also been shown to exist in humans. Studies suggest that the glymphatic system may be involved in the pathophysiological processes of neurological pathologies, such as degenerative brain disorders and normal pressure hydrocephalus (NPH), but also in the aftermath of ischemic stroke, subarachnoidal hemorrhage and traumatic brain injury. It is believed that the glymphatic system with its cleansing capabilities is upregulated during sleep, and interestingly studies show association between lack of sleep and neurodegenerative diseases. In this article, we present an overview of the glymphatic system and its possible role in intracranial pathologies.

Could dexmedetomidine be repurposed as a glymphatic enhancer?

Cerebrospinal fluid (CSF) flows through the central nervous system (CNS) via the glymphatic pathway to clear the interstitium of metabolic waste. In preclinical studies, glymphatic fluid flow rate increases with low central noradrenergic tone and slow-wave activity during natural sleep and general anesthesia. By contrast, sleep deprivation reduces glymphatic clearance and leads to intracerebral accumulation of metabolic waste, suggesting an underlying mechanism linking sleep disturbances with neurodegenerative diseases. The selective α2-adrenergic agonist dexmedetomidine is a sedative drug that induces slow waves in the electroencephalogram, suppresses central noradrenergic tone, and preserves glymphatic outflow. As recently developed dexmedetomidine formulations enable self-administration, we suggest that dexmedetomidine could serve as a sedative-hypnotic drug to enhance clearance of harmful waste from the brain of those vulnerable to neurodegeneration.

The glymphatic system: implications for drugs for central nervous system diseases.

In the past decade, evidence for a fluid clearance pathway in the central nervous system known as the glymphatic system has grown. According to the glymphatic system concept, cerebrospinal fluid flows directionally through the brain and non-selectively clears the interstitium of metabolic waste. Importantly, the glymphatic system may be modulated by particular drugs such as anaesthetics, as well as by non-pharmacological factors such as sleep, and its dysfunction has been implicated in central nervous system disorders such as Alzheimer disease. Although the glymphatic system is best described in rodents, reports using multiple neuroimaging modalities indicate that a similar transport system exists in the human brain. Here, we overview the evidence for the glymphatic system and its role in disease and discuss opportunities to harness the glymphatic system therapeutically; for example, by improving the effectiveness of intrathecally delivered drugs.

[Glymphatic system]. / Glimfaticheskaya sistema.

Glymphatic system - is a recently discovered system for waste clearance and solute balance regulation in the brain. In this article we review the modern views on anatomy and physiology of glymphatic system, the factors known to regulate glymphatic flow, as well as the role of glyphatic dysfunction in the development of central nervous system pathology.