scholarly journals Glymphatic System as a Gateway to Connect Neurodegeneration From Periphery to CNS

2021 ◽  
Vol 15 ◽  
Author(s):  
Gianfranco Natale ◽  
Fiona Limanaqi ◽  
Carla L. Busceti ◽  
Federica Mastroiacovo ◽  
Ferdinando Nicoletti ◽  
...  
Keyword(s):  
Interstitial Fluid ◽  
Lymphatic Vessels ◽  
Normal Pressure ◽  
Lymphatic Drainage ◽  
Brain Parenchyma ◽  
Waste Products ◽  
Pathological Conditions ◽  
The Central Nervous System ◽  
Glymphatic Pathway ◽  
The Brain

The classic concept of the absence of lymphatic vessels in the central nervous system (CNS), suggesting the immune privilege of the brain in spite of its high metabolic rate, was predominant until recent times. On the other hand, this idea left questioned how cerebral interstitial fluid is cleared of waste products. It was generally thought that clearance depends on cerebrospinal fluid (CSF). Not long ago, an anatomically and functionally discrete paravascular space was revised to provide a pathway for the clearance of molecules drained within the interstitial space. According to this model, CSF enters the brain parenchyma along arterial paravascular spaces. Once mixed with interstitial fluid and solutes in a process mediated by aquaporin-4, CSF exits through the extracellular space along venous paravascular spaces, thus being removed from the brain. This process includes the participation of perivascular glial cells due to a sieving effect of their end-feet. Such draining space resembles the peripheral lymphatic system, therefore, the term “glymphatic” (glial-lymphatic) pathway has been coined. Specific studies focused on the potential role of the glymphatic pathway in healthy and pathological conditions, including neurodegenerative diseases. This mainly concerns Alzheimer’s disease (AD), as well as hemorrhagic and ischemic neurovascular disorders; other acute degenerative processes, such as normal pressure hydrocephalus or traumatic brain injury are involved as well. Novel morphological and functional investigations also suggested alternative models to drain molecules through perivascular pathways, which enriched our insight of homeostatic processes within neural microenvironment. Under the light of these considerations, the present article aims to discuss recent findings and concepts on nervous lymphatic drainage and blood–brain barrier (BBB) in an attempt to understand how peripheral pathological conditions may be detrimental to the CNS, paving the way to neurodegeneration.

scholarly journals Brain lymphatic drainage system – visualization opportunities and current state of the art

2020 ◽  
Vol 9 (3) ◽  
pp. 81-89
Author(s):  
G. S. Yankova ◽  
O. B. Bogomyakova
Keyword(s):  
Neurodegenerative Diseases ◽  
Immune Surveillance ◽  
Lymphatic Vessels ◽  
Drainage System ◽  
Lymphatic Drainage ◽  
Waste Products ◽  
Glymphatic System ◽  
Age Related ◽  
The Central Nervous System ◽  
The Brain

The lymphatic drainage system of the brain is assumed to consist of the lymphatic system and a network of meningeal lymphatic vessels. This system supports brain homeostasis, participates in immune surveillance and presents a new therapeutic target in the treatment of neurological disorders.The article analyzes and systematizes data on the brain lymphatic drainage system. The key components of this system are considered: recently described meningeal lymphatic vessels and their relationship with the glymphatic system, which provides perfusion of the central nervous system with cerebrospinal and interstitial fluids. The lymphatic drainage system helps to maintain water and ion balances of the interstitial fluid and to remove metabolic waste products, assists in reabsorption of macromolecules. Disorders in its work play a crucial role in age-related changes in the brain, the pathogenesis of neurovascular and neurodegenerative diseases, as well as injuries and brain tumors. The review also presents the results of human studies concerning the presence, anatomy and structure of meningeal lymphatic vessels and the glymphatic system. The discovery of the brain lymphatic drainage system has not only changed our understanding of cerebrospinal fluid circulation, but also contributed to understanding the pathology and mechanisms of neurodegenerative diseases.

scholarly journals Cerebrospinal Fluid and Interstitial Fluid Motion via the Glymphatic Pathway Modelled by Optimal Mass Transport

2016 ◽  
Author(s):  
Vadim Ratner ◽  
Yi Gao ◽  
Hedok Lee ◽  
Maikan Nedergaard ◽  
Helene Benveniste ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Interstitial Fluid ◽  
Initial Conditions ◽  
Fluid Motion ◽  
Flow Patterns ◽  
Brain Parenchyma ◽  
Fluid Exchange ◽  
Waste Products ◽  
Glymphatic Pathway ◽  
The Brain

It was recently shown that the brain-wide cerebrospinal fluid (CSF) and interstitial fluid exchange system designated the `glymphatic pathway' plays a key role in removing waste products from the brain, similarly to the lymphatic system in other body organs [1,2]. It is therefore important to study the flow patterns of glymphatic transport through the live brain in order to better understand its functionality in normal and pathological states. Unlike blood, the CSF does not flow rapidly through a network of dedicated vessels, but rather through peri-vascular channels and brain parenchyma in a slower time-domain, and thus conventional fMRI or other blood-flow sensitive MRI sequences do not provide much useful information about the desired flow patterns. We have accordingly analyzed a series of MRI images, taken at different times, of the brain of a live rat, which was injected with a paramagnetic tracer into the CSF via the lumbar intrathecal space of the spine. Our goal is twofold: (a) find glymphatic (tracer) flow directions in the live rodent brain; and (b) provide a model of a (healthy) brain that will allow the prediction of tracer concentrations given initial conditions. We model the liquid flow through the brain by the diffusion equation. We then use the Optimal Mass Transfer (OMT) approach [3] to model the glymphatic flow vector field, and estimate the diffusion tensors by analyzing the (changes in the) flow. Simulations show that the resulting model successfully reproduces the dominant features of the experimental data.

scholarly journals Does Impaired Glymphatic Drainage Cause Glymphedema? A Review Tailored to Neurocritical Care and Neurosurgery

2021 ◽  
Author(s):  
Paul T. Akins ◽  
Kern H. Guppy
Keyword(s):  
Neurocritical Care ◽  
Normal Pressure ◽  
Lymphatic Drainage ◽  
Brain Parenchyma ◽  
Therapeutic Approaches ◽  
Cerebrospinal Fluid Circulation ◽  
Glymphatic System ◽  
New Therapeutic Approaches ◽  
The Central Nervous System ◽  
Glymphatic Pathway

AbstractResearch into the glymphatic system reached an inflection point with steep trajectory in 2012 when it was formally recognized and named, but the historical roots for it are solid and deep, dating back to pioneers such as Cushing, Weed, and Dandy. We provide an overview of key discoveries of the glymphatic system, which promotes bulk flow of fluid and solutes throughout the brain parenchyma. We also discuss the lymphatic drainage of the central nervous system. Evidence is building that failure of the glymphatic system causes glymphedema in patients commonly managed by neurocritical care and neurosurgery specialists. We review research supporting this for decompressive craniectomy, subarachnoid hemorrhage, and normal-pressure hydrocephalus. We argue that it is time for a paradigm shift from the traditional model of cerebrospinal fluid circulation to a revised model that incorporates the glymphatic pathway and lymphatic clearance. These recent breakthroughs will inspire new therapeutic approaches to recognize, reverse, and restore glymphatic dysfunction and to leverage this pathway to deliver brain-wide therapeutics.

scholarly journals The brain’sglymphatic system:physiological anatomy and clinical perspectives

2018 ◽  
Vol 10 (4) ◽  
pp. 94-100 ◽  
Author(s):  
V. N. Nikolenko ◽  
M. V. Oganesyan ◽  
N. N. Yakhno ◽  
E. A. Orlov ◽  
E. E. Porubayeva ◽  
...  
Keyword(s):  
Interstitial Fluid ◽  
Cerebral Arteries ◽  
Lymphatic Vessels ◽  
Circulatory System ◽  
Brain Parenchyma ◽  
Special Role ◽  
Close Link ◽  
New Therapeutic Approaches ◽  
The Central Nervous System ◽  
The Brain

The recently discovered glymphatic system (GS) ensures the efficient clearance of interstitial fluid and soluble compounds from the central nervous system into cerebrospinal fluid (CSF), which compensates for the lack of conventional lymphatic vessels in the brain parenchyma. This unique anatomical and physiological phenomenon had been unknown until 2012. GS lacks inherent proper vessels Р the current of CSF and interstitial fluid is carried out directly inside the arterial walls (the perivascular pathway) or near the walls of the cerebral arteries and veins (the paravascular pathway). Current biorheological technologies could establish a special role of aquaporin-4 in the filtration of CSF and interstitial fluid. The close link between GS and the CSF circulatory system allows the established views on fluid dynamics within the brain to be reconsidered. The discovery of GS can contribute to our understanding of the pathogenesis of increased intracranial pressure and neurodegenerative diseases, as well as to the elaboration of new therapeutic approaches to their treatment.

scholarly journals The Glymphatic System: A Review

2018 ◽  
Vol 37 (03) ◽  
pp. 190-195 ◽  
Author(s):  
Louise Oliveira ◽  
Eberval Figueiredo ◽  
Carlos Peres
Keyword(s):  
Lymphatic Vessels ◽  
Normal Pressure ◽  
Therapeutic Interventions ◽  
Glymphatic System ◽  
Adult Body Mass ◽  
System A ◽  
Optimal Function ◽  
The Central Nervous System ◽  
Glymphatic Pathway ◽  
The One

AbstractThe brain represents ∼ 2% of the adult body mass; conversely, it is responsible for 20% to 25% of the glucose and 20% of the oxygen consumption, receiving 15% of the cardiac output. This substantial metabolic rate is associated with a significant production of biological debris, which is potentially toxic. Therefore, a complex and efficient clearance system is required to prevent the accumulation of byproducts and ensure optimal function. However, until today, there is little knowledge about this topic. The glymphatic system, also known as perivascular pathway, is a recently described glial-dependent network that is responsible for the clearance of metabolites from the central nervous system (CNS), playing a role equivalent to the one played by the lymphatic vessels present in other organs. Studies have demonstrated that the glymphatic pathway has a paramount role in protein homeostasis, and that the malfunction of this system may be related to the development of neurodegenerative disorders such as Alzheimer disease and normal pressure hydrocephalus. They also showed that body posture, exercise and the state of consciousness influence the glymphatic transport. In this context, the understanding of this clearance system could not only clarify the pathophysiology of several diseases, but also contribute to future therapeutic interventions. In the present article, we will evaluate the glymphatic pathway, focusing on the factors that regulate its flow, as well as on its role in CNS physiology and in disease initiation and progression, including dementia, hydrocephalus, glaucoma and traumatic brain injury. Ultimately, this review also aims to encourage further research on novel therapeutic targets.

scholarly journals Cerebral Vessels: An Overview of Anatomy, Physiology, and Role in the Drainage of Fluids and Solutes

2021 ◽  
Vol 11 ◽  
Author(s):  
Nivedita Agarwal ◽  
Roxana Octavia Carare
Keyword(s):  
Cerebral Arteries ◽  
Lymphatic Vessels ◽  
Vascular Anatomy ◽  
Brain Perfusion ◽  
Brain Parenchyma ◽  
Basement Membranes ◽  
Cervical Lymph Nodes ◽  
Waste Products ◽  
Venous Sinuses ◽  
The Brain

The cerebral vasculature is made up of highly specialized structures that assure constant brain perfusion necessary to meet the very high demand for oxygen and glucose by neurons and glial cells. A dense, redundant network of arteries is spread over the entire pial surface from which penetrating arteries dive into the cortex to reach the neurovascular units. Besides providing blood to the brain parenchyma, cerebral arteries are key in the drainage of interstitial fluid (ISF) and solutes such as amyloid-beta. This occurs along the basement membranes surrounding vascular smooth muscle cells, toward leptomeningeal arteries and deep cervical lymph nodes. The dense microvasculature is made up of fine capillaries. Capillary walls contain pericytes that have contractile properties and are lined by a highly specialized blood–brain barrier that regulates the entry of solutes and ions and maintains the integrity of the composition of ISF. They are also important for the production of ISF. Capillaries drain into venules that course centrifugally toward the cortex to reach cortical veins and empty into dural venous sinuses. The walls of the venous sinuses are also home to meningeal lymphatic vessels that support the drainage of cerebrospinal fluid, although such pathways are still poorly understood. Damage to macro- and microvasculature will compromise cerebral perfusion, hamper the highly synchronized movement of neurofluids, and affect the drainage of waste products leading to neuronal and glial degeneration. This review will present vascular anatomy, their role in fluid dynamics, and a summary of how their dysfunction can lead to neurodegeneration.

scholarly journals Waste Clearance in the Brain

2021 ◽  
Vol 15 ◽  
Author(s):  
Jasleen Kaur ◽  
Lara M. Fahmy ◽  
Esmaeil Davoodi-Bojd ◽  
Li Zhang ◽  
Guangliang Ding ◽  
...  
Keyword(s):  
Interstitial Fluid ◽  
Lymphatic Vessels ◽  
Brain Parenchyma ◽  
Perivascular Spaces ◽  
Future Directions ◽  
Relevant Role ◽  
Healthy Functioning ◽  
The Brain ◽  
Brain Homeostasis

Waste clearance (WC) is an essential process for brain homeostasis, which is required for the proper and healthy functioning of all cerebrovascular and parenchymal brain cells. This review features our current understanding of brain WC, both within and external to the brain parenchyma. We describe the interplay of the blood-brain barrier (BBB), interstitial fluid (ISF), and perivascular spaces within the brain parenchyma for brain WC directly into the blood and/or cerebrospinal fluid (CSF). We also discuss the relevant role of the CSF and its exit routes in mediating WC. Recent discoveries of the glymphatic system and meningeal lymphatic vessels, and their relevance to brain WC are highlighted. Controversies related to brain WC research and potential future directions are presented.

scholarly journals A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules

2015 ◽  
Vol 212 (7) ◽  
pp. 991-999 ◽  
Author(s):  
Aleksanteri Aspelund ◽  
Salli Antila ◽  
Steven T. Proulx ◽  
Tine Veronica Karlsen ◽  
Sinem Karaman ◽  
...  
Keyword(s):  
Subarachnoid Space ◽  
Interstitial Fluid ◽  
Vascular System ◽  
Lymphatic Vessels ◽  
Cervical Lymph Nodes ◽  
Brain Interstitial Fluid ◽  
Lymphatic Vasculature ◽  
The Central Nervous System ◽  
Base Of The Skull ◽  
The Brain

The central nervous system (CNS) is considered an organ devoid of lymphatic vasculature. Yet, part of the cerebrospinal fluid (CSF) drains into the cervical lymph nodes (LNs). The mechanism of CSF entry into the LNs has been unclear. Here we report the surprising finding of a lymphatic vessel network in the dura mater of the mouse brain. We show that dural lymphatic vessels absorb CSF from the adjacent subarachnoid space and brain interstitial fluid (ISF) via the glymphatic system. Dural lymphatic vessels transport fluid into deep cervical LNs (dcLNs) via foramina at the base of the skull. In a transgenic mouse model expressing a VEGF-C/D trap and displaying complete aplasia of the dural lymphatic vessels, macromolecule clearance from the brain was attenuated and transport from the subarachnoid space into dcLNs was abrogated. Surprisingly, brain ISF pressure and water content were unaffected. Overall, these findings indicate that the mechanism of CSF flow into the dcLNs is directly via an adjacent dural lymphatic network, which may be important for the clearance of macromolecules from the brain. Importantly, these results call for a reexamination of the role of the lymphatic system in CNS physiology and disease.

scholarly journals The Brain Entangled: The Contribution of Neutrophil Extracellular Traps to the Diseases of the Central Nervous System

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1477 ◽  
Author(s):  
Aneta Manda-Handzlik ◽  
Urszula Demkow
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Proteolytic Enzymes ◽  
Neutrophil Extracellular Traps ◽  
Brain Parenchyma ◽  
Free Oxygen Radicals ◽  
Extracellular Traps ◽  
Pathological Conditions ◽  
The Central Nervous System ◽  
The Brain

Under normal conditions, neutrophils are restricted from trafficking into the brain parenchyma and cerebrospinal fluid by the presence of the brain–blood barrier (BBB). Yet, infiltration of the central nervous system (CNS) by neutrophils is a well-known phenomenon in the course of different pathological conditions, e.g., infection, trauma or neurodegeneration. Different studies have shown that neutrophil products, i.e., free oxygen radicals and proteolytic enzymes, play an important role in the pathogenesis of BBB damage. It was recently observed that accumulating granulocytes may release neutrophil extracellular traps (NETs), which damage the BBB and directly injure surrounding neurons. In this review, we discuss the emerging role of NETs in various pathological conditions affecting the CNS.

scholarly journals Neuroinflammation-Driven Lymphangiogenesis in CNS Diseases

2021 ◽  
Vol 15 ◽  
Author(s):  
Martin Hsu ◽  
Collin Laaker ◽  
Matyas Sandor ◽  
Zsuzsanna Fabry
Keyword(s):  
Brain Injury ◽  
Lymphatic Vessels ◽  
Brain Parenchyma ◽  
Cribriform Plate ◽  
Cns Infection ◽  
Cns Diseases ◽  
The Central Nervous System ◽  
The Many ◽  
Antigen Presenting ◽  
The Brain

The central nervous system (CNS) undergoes immunosurveillance despite the lack of conventional antigen presenting cells and lymphatic vessels in the CNS parenchyma. Additionally, the CNS is bathed in a cerebrospinal fluid (CSF). CSF is continuously produced, and consequently must continuously clear to maintain fluid homeostasis despite the lack of conventional lymphatics. During neuroinflammation, there is often an accumulation of fluid, antigens, and immune cells to affected areas of the brain parenchyma. Failure to effectively drain these factors may result in edema, prolonged immune response, and adverse clinical outcome as observed in conditions including traumatic brain injury, ischemic and hypoxic brain injury, CNS infection, multiple sclerosis (MS), and brain cancer. Consequently, there has been renewed interest surrounding the expansion of lymphatic vessels adjacent to the CNS which are now thought to be central in regulating the drainage of fluid, cells, and waste out of the CNS. These lymphatic vessels, found at the cribriform plate, dorsal dural meninges, base of the brain, and around the spinal cord have each been implicated to have important roles in various CNS diseases. In this review, we discuss the contribution of meningeal lymphatics to these processes during both steady-state conditions and neuroinflammation, as well as discuss some of the many still unknown aspects regarding the role of meningeal lymphatics in neuroinflammation. Specifically, we focus on the observed phenomenon of lymphangiogenesis by a subset of meningeal lymphatics near the cribriform plate during neuroinflammation, and discuss their potential roles in immunosurveillance, fluid clearance, and access to the CSF and CNS compartments. We propose that manipulating CNS lymphatics may be a new therapeutic way to treat CNS infections, stroke, and autoimmunity.

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