Glymphatic system

Glymphatic system
Glymphatic system
	Mammalian glymphatic system
Identifiers
MeSH	D000077502
	Anatomical terminology [ edit on Wikidata]

Last updated January 13, 2025

The glymphatic system, glymphatic clearance pathway or paravascular system is an organ system for metabolic waste removal in the central nervous system (CNS) of vertebrates. According to this model, cerebrospinal fluid (CSF), an ultrafiltrated plasma fluid secreted by choroid plexuses in the cerebral ventricles, flows into the paravascular space around cerebral arteries, contacts and mixes with interstitial fluid (ISF) and solutes within the brain parenchyma, and exits via the cerebral venous paravascular spaces back into the subarachnoid space.^[1] The pathway consists of a para-arterial influx mechanism for CSF driven primarily by arterial pulsation ^[2], which "massages" the low-pressure CSF into the denser brain parenchyma, and the CSF flow is regulated during sleep by changes in parenchyma resistance due to expansion and contraction of the extracellular space. Clearance of soluble proteins, metabolites and excess extracellular fluid is accomplished through convective bulk flow of ISF, facilitated by astrocytic aquaporin 4 (AQP4) water channels.^[3]

Proposed structure

Astrocytes stained for GFAP (green) and aquaporin-4 (purple) Astrocytes.jpg — Astrocytes stained for GFAP (green) and aquaporin-4 (purple)

In a study published in 2012,^[5] a group of researchers from the University of Rochester, headed by Maiken Nedergaard, used in-vivo two-photon imaging of small fluorescent tracers to monitor the flow of subarachnoid CSF into and through the brain parenchyma. The two-photon microscopy allowed the Rochester team to visualize the flux of CSF in living mice, in real time, without needing to puncture the CSF compartment (imaging was performed through a closed cranial window). According to findings of that study, subarachnoid CSF enters the brain rapidly, along the paravascular spaces surrounding the penetrating arteries, then exchanges with the surrounding interstitial fluid.^[5] Similarly, interstitial fluid is cleared from the brain parenchyma via the paravascular spaces surrounding large draining veins.^{[ citation needed ]}

Paravascular spaces are CSF-filled channels formed between the brain blood vessels and leptomeningeal sheathes that surround cerebral surface vessels and proximal penetrating vessels. Around these penetrating vessels, paravascular spaces take the form of Virchow-Robin spaces. Where the Virchow-Robin spaces terminate within the brain parenchyma, paravascular CSF can continue traveling along the basement membranes surrounding arterial vascular smooth muscle, to reach the basal lamina surrounding brain capillaries. CSF movement along these paravascular pathways is rapid and arterial pulsation has long been suspected as an important driving force for paravascular fluid movement.^[6] In a study published in 2013, J. Iliff and colleagues demonstrated this directly. Using in vivo 2-photon microscopy, the authors reported that when cerebral arterial pulsation was either increased or decreased, the rate of paravacular CSF flux in turn increased or decreased, respectively.^{[ citation needed ]}

Astrocytes extend long processes that interface with neuronal synapses, as well as projections referred to as 'end-feet' that completely ensheathe the brain's entire vasculature. Astrocytes are known to facilitate changes in blood flow ^[7]^[8] and have long been thought to play a role in waste removal in the brain.^[9] Astrocytes express water channels called aquaporins.^[10] Until 2000, no physiological function had been identified that explained their presence in the mammalian CNS. Aquaporins are membrane-bound channels and regulate the flux of water into and out of cells. Relative to simple diffusion, they increases water permeability 3– to 10-fold.^[11] The two types of aquaporins expressed in the CNS are aquaporin-1, which is expressed by specialized epithelial cells of the choroid plexus, and aquaporin-4 (AQP4), which is expressed by astrocytes.^[12]^[13] Aquaporin-4 expression in astrocytes is highly polarized to the endfoot processes ensheathing the cerebral vasculature. Up to 50% of the vessel-facing endfoot surface that faces the vasculature is occupied by orthogonal arrays of AQP4.^[10]^[12] In 2012, it was shown that AQP4 is essential for paravascular CSF–ISF exchange. Analysis of genetically modified mice that lacked the AQP4 gene revealed that the bulk flow-dependent clearance of interstitial solutes decreases by 70% in the absence of AQP4. Based upon this role of AQP4-dependent glial water transport in the process of paravascular interstitial solute clearance, Iliff and Nedergaard termed this brain-wide glio-vascular pathway the "glymphatic system".

Function

Waste clearance during sleep

A publication by L. Xie and colleagues in 2013 explored the efficiency of the glymphatic system during slow wave sleep and provided the first direct evidence that the clearance of interstitial waste products increases during the resting state. Using a combination of diffusion iontophoresis techniques pioneered by Nicholson and colleagues, in vivo 2-photon imaging, and electroencephalography to confirm the wake and sleep states, Xia and Nedergaard demonstrated that the changes in efficiency of CSF–ISF exchange between the awake and sleeping brain were caused by expansion and contraction of the extracellular space, which increased by ~60% in the sleeping brain to promote clearance of interstitial wastes such as amyloid beta. On the basis of these findings, they hypothesized that the restorative properties of sleep may be linked to increased glymphatic clearance of metabolic waste products produced by neural activity in the awake brain.^[14]

Lipid transport

Another key function of the glymphatic system was documented by Thrane et al., who, in 2013, demonstrated that the brain's system of paravascular pathways plays an important role in transporting small lipophilic molecules.^[15]

Led by M. Nedergaard, Thrane and colleagues also showed^{[ when? ]} that the paravascular transport of lipids through the glymphatic pathway activated glial calcium signalling and that the depressurization of the cranial cavity, and thus impairment of the glymphatic circulation, led to unselective lipid diffusion, intracellular lipid accumulation, and pathological signalling among astrocytes.^{[ citation needed ]}

Although further experiments are needed to parse out the physiological significance of the connection between the glymphatic circulation, calcium signalling, and paravascular lipid transport in the brain, the findings point to the adoption of a function in the CNS similar to the capacity of the intestinal lymph vessels (lacteals) to carry lipids to the liver.^{[ citation needed ]}

Clinical significance

Pathologically, neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and Huntington's disease are all characterized by the progressive loss of neurons, cognitive decline, motor impairments, and sensory loss.^[16]^[17] Collectively these diseases fall within a broad category referred to as proteinopathies due to the common assemblage of misfolded or aggregated intracellular or extracellular proteins. According to the prevailing amyloid hypothesis of Alzheimer's disease, the aggregation of amyloid-beta (a peptide normally produced in and cleared from the healthy young brain) into extracellular plaques drives the neuronal loss and brain atrophy that is the hallmark of Alzheimer's dementia. Although the full extent of the involvement of the glymphatic system in Alzheimer's disease and other neurodegenerative disorders remains unclear, researchers have demonstrated through experiments with genetically modified mice that the proper function of the glymphatic clearance system was necessary to remove soluble amyloid-beta from the brain interstitium.^[5] In mice that lack the AQP4 gene, amyloid-beta clearance is reduced by approximately 55 percent.

The glymphatic system also may be impaired after acute brain injuries such as ischemic stroke, intracranial hemorrhage, or subarachnoid hemorrhage. In 2014, a group of researchers from the French Institute of Health and Medical Research (INSERM) demonstrated by MRI that the glymphatic system was impaired after subarachnoid hemorrhage, because of the presence of coagulated blood in the paravascular spaces.^[18] Injection of tissue plasminogen activator (a fibrinolytic drug) in the CSF improved glymphatic functioning. In a parallel study, they also demonstrated that the glymphatic system was impaired after ischemic stroke in the ischemic hemisphere, although the pathophysiological basis of this phenomenon remains unclear. Notably, recanalization of the occluded artery also reestablished the glymphatic flow.

The glymphatic system may also be involved in the pathogenesis of amyotrophic lateral sclerosis.^[19]

History

Discovery and description of cerebrospinal fluid

Although the first known observations of the CSF date back to Hippocrates (460–375 BCE) and later, to Galen (130–200 CE), its discovery is credited to Emanuel Swedenborg (1688–1772 CE), who, being a devoutly religious man, identified the CSF during his search for the seat of the soul.^[20] The 16 centuries of anatomists who came after Hippocrates and Galen may have missed identifying the CSF due to the prevailing autopsy technique of the time, which included severing the head and draining the blood before dissecting the brain.^[20] Although Swedenborg's work (in translation) was not published until 1887 due to his lack of medical credentials, he also may have made the first connection between the CSF and the lymphatic system. His description of the CSF was of a "spirituous lymph".^[20]

CNS lymphatics

In 2015, the presence of a meningeal lymphatic system was first identified.^[21]^[22] Downstream of the glymphatic system's waste clearance from the ISF to the CSF, the meningeal lymphatic system drains fluid from the glymphatic system to the meningeal compartment and deep cervical lymph nodes; this is shown by the draining of fluorescent dyes injected intracisternally into the CSF in mice.^[21] The meningeal lymphatics also carry immune cells.^[21] The extent to which these cells may interact directly with the brain or glymphatic system, is unknown.^{[ citation needed ]}

Diffusion hypothesis

For more than a century the prevailing hypothesis was that the flow of cerebrospinal fluid (CSF), which surrounds, but does not come in direct contact with the parenchyma of the CNS, could replace peripheral lymphatic functions and play an important role in the clearance of extracellular solutes.^[23] The majority of the CSF is formed in the choroid plexus and flows through the brain along a distinct pathway: moving through the cerebral ventricular system, into the subarachnoid space surrounding the brain, then draining into the systemic blood column via arachnoid granulations of the dural sinuses or to peripheral lymphatics along cranial nerve sheathes.^[24]^[25] Many researchers suggested that the CSF compartment constitutes a sink for interstitial solute and fluid clearance from the brain parenchyma.^{[ citation needed ]} However, the distances between the interstitial fluid and the CSF in the ventricles and subarachnoid space are too great for the efficient removal of interstitial macromolecules and wastes by simple diffusion alone.^{[ citation needed ]} In 1971, Helen Cserr at Brown University calculated that mean diffusion times for large molecules, such as albumin, would exceed 100 hours to traverse 1 cm of brain tissue,^[26] a rate that is not compatible with the intense metabolic demands of brain tissue. Additionally, a clearance system based on simple diffusion would lack the sensitivity to respond rapidly to deviations from homeostatic conditions.^{[ citation needed ]} As an alternative explanation to diffusion, Cserr and colleagues proposed that convective bulk flow of interstitial fluid from the brain parenchyma to the CSF was responsible for efficient waste clearance.^[26]

Key determinants of diffusion through the brain interstitial spaces are the dimensions and composition of the extracellular compartment. In a series of elegantly designed experiments in the 1980s and 1990s, researchers from New York University explored the microenvironment of the extracellular space using ion-selective micropipettes and ionophoretic point sources. They showed that solute and water movement through the brain parenchyma slows as the extracellular volume fraction decreases and becomes more tortuous.^[27]

Paravascular channels

The continuity between the brain interstitial fluid and CSF was confirmed in 1981 by evidence that interstitial solutes in the brain exchange with CSF via a bulk flow mechanism, rather than by diffusion.^[28] Studies in 1985 indicated that cerebrospinal fluid and interstitial fluid may flow along specific anatomical pathways within the brain, with CSF moving into the brain along the outside of blood vessels; such 'paravascular channels' were possibly analogous to peripheral lymph vessels, facilitating the clearance of interstitial wastes from the brain.^[6]^[29] However, other studies did not observe such widespread paravascular CSF–ISF exchange.^[30]^[28]

Dural sinuses and meninges

Glymphatic flow was initially believed to be the complete answer to the long-standing question of how the sensitive neural tissue of the CNS functions in the perceived absence of a lymphatic drainage pathway for extracellular proteins, excess fluid, and metabolic waste products. In 2015, two subsequent articles by Louveau et al. from the University of Virginia School of Medicine ^[21] and Aspelund et al. from the University of Helsinki reported independently that the dural sinuses and meningeal arteries are lined with conventional lymphatic vessels, and that this long-elusive vasculature forms a connecting pathway to the glymphatic system.^[22]

Related Research Articles

Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates.

Hydrocephalus is a condition in which an accumulation of cerebrospinal fluid (CSF) occurs within the brain. This typically causes increased pressure inside the skull. Older people may have headaches, double vision, poor balance, urinary incontinence, personality changes, or mental impairment. In babies, it may be seen as a rapid increase in head size. Other symptoms may include vomiting, sleepiness, seizures, and downward pointing of the eyes.

<span class="mw-page-title-main">Ventricular system</span> Structures containing cerebrospinal fluid

In neuroanatomy, the ventricular system is a set of four interconnected cavities known as cerebral ventricles in the brain. Within each ventricle is a region of choroid plexus which produces the circulating cerebrospinal fluid (CSF). The ventricular system is continuous with the central canal of the spinal cord from the fourth ventricle, allowing for the flow of CSF to circulate.

Lymph is the fluid that flows through the lymphatic system, a system composed of lymph vessels (channels) and intervening lymph nodes whose function, like the venous system, is to return fluid from the tissues to be recirculated. At the origin of the fluid-return process, interstitial fluid—the fluid between the cells in all body tissues—enters the lymph capillaries. This lymphatic fluid is then transported via progressively larger lymphatic vessels through lymph nodes, where substances are removed by tissue lymphocytes and circulating lymphocytes are added to the fluid, before emptying ultimately into the right or the left subclavian vein, where it mixes with central venous blood.

Cerebral edema is excess accumulation of fluid (edema) in the intracellular or extracellular spaces of the brain. This typically causes impaired nerve function, increased pressure within the skull, and can eventually lead to direct compression of brain tissue and blood vessels. Symptoms vary based on the location and extent of edema and generally include headaches, nausea, vomiting, seizures, drowsiness, visual disturbances, dizziness, and in severe cases, death.

<span class="mw-page-title-main">Pia mater</span> Delicate innermost layer of the meninges, the membranes surrounding the brain and spinal cord

Pia mater, often referred to as simply the pia, is the delicate innermost layer of the meninges, the membranes surrounding the brain and spinal cord. Pia mater is medieval Latin meaning "tender mother". The other two meningeal membranes are the dura mater and the arachnoid mater. Both the pia and arachnoid mater are derivatives of the neural crest while the dura is derived from embryonic mesoderm. The pia mater is a thin fibrous tissue that is permeable to water and small solutes. The pia mater allows blood vessels to pass through and nourish the brain. The perivascular space between blood vessels and pia mater is proposed to be part of a pseudolymphatic system for the brain. When the pia mater becomes irritated and inflamed the result is meningitis.

The human brain is the central organ of the human nervous system, and with the spinal cord, comprises the central nervous system. It consists of the cerebrum, the brainstem and the cerebellum. The brain controls most of the activities of the body, processing, integrating, and coordinating the information it receives from the sensory nervous system. The brain integrates the instructions sent to the rest of the body. The brain is contained in, and protected by, the skull of the head.

<span class="mw-page-title-main">Arachnoid granulation</span> Protrusions of the arachnoid mater for returning cerebrospinal fluid to circulation

Arachnoid granulations are small outpouchings of the arachnoid mater and subarachnoid space into the dural venous sinuses of the brain. The granulations are thought to mediate the draining of cerebrospinal fluid (CSF) from the subarachnoid space into the venous system.

<span class="mw-page-title-main">Choroid plexus</span> Structure in the ventricles of the brain

The choroid plexus, or plica choroidea, is a plexus of cells that arises from the tela choroidea in each of the ventricles of the brain. Regions of the choroid plexus produce and secrete most of the cerebrospinal fluid (CSF) of the central nervous system. The choroid plexus consists of modified ependymal cells surrounding a core of capillaries and loose connective tissue. Multiple cilia on the ependymal cells move to circulate the cerebrospinal fluid.

The syndrome of inappropriate antidiuretic hormone secretion (SIADH), also known as the syndrome of inappropriate antidiuresis (SIAD), is characterized by a physiologically inappropriate release of antidiuretic hormone (ADH) either from the posterior pituitary gland, or an abnormal non-pituitary source. Unsuppressed ADH causes a physiologically inappropriate increase in solute-free water being reabsorbed by the tubules of the kidney to the venous circulation leading to hypotonic hyponatremia.

<span class="mw-page-title-main">Perivascular space</span> Space surrounding blood vessels

A perivascular space, also known as a Virchow–Robin space, is a fluid-filled space surrounding certain blood vessels in several organs, including the brain, potentially having an immunological function, but more broadly a dispersive role for neural and blood-derived messengers. The brain pia mater is reflected from the surface of the brain onto the surface of blood vessels in the subarachnoid space. In the brain, perivascular cuffs are regions of leukocyte aggregation in the perivascular spaces, usually found in patients with viral encephalitis.

The interstitium is a contiguous fluid-filled space existing between a structural barrier, such as a cell membrane or the skin, and internal structures, such as organs, including muscles and the circulatory system. The fluid in this space is called interstitial fluid, comprises water and solutes, and drains into the lymph system. The interstitial compartment is composed of connective and supporting tissues within the body – called the extracellular matrix – that are situated outside the blood and lymphatic vessels and the parenchyma of organs. The role of the interstitium in solute concentration, protein transport and hydrostatic pressure impacts human pathology and physiological responses such as edema, inflammation and shock.

Aquaporin-4, also known as AQP-4, is a water channel protein encoded by the AQP4 gene in humans. AQP-4 belongs to the aquaporin family of integral membrane proteins that conduct water through the cell membrane. A limited number of aquaporins are found within the central nervous system (CNS): AQP1, 3, 4, 5, 8, 9, and 11, but more exclusive representation of AQP1, 4, and 9 are found in the brain and spinal cord. AQP4 shows the largest presence in the cerebellum and spinal cord grey matter. In the CNS, AQP4 is the most prevalent aquaporin channel, specifically located at the perimicrovessel astrocyte foot processes, glia limitans, and ependyma. In addition, this channel is commonly found facilitating water movement near cerebrospinal fluid and vasculature.

The glia limitans, or the glial limiting membrane, is a thin barrier of astrocyte foot processes associated with the parenchymal basal lamina surrounding the brain and spinal cord. It is the outermost layer of neural tissue, and among its responsibilities is the prevention of the over-migration of neurons and neuroglia, the supporting cells of the nervous system, into the meninges. The glia limitans also plays an important role in regulating the movement of small molecules and cells into the brain tissue by working in concert with other components of the central nervous system (CNS) such as the blood–brain barrier (BBB).

<span class="mw-page-title-main">Fluid compartments</span> Conceptual divisions of a living body

The human body and even its individual body fluids may be conceptually divided into various fluid compartments, which, although not literally anatomic compartments, do represent a real division in terms of how portions of the body's water, solutes, and suspended elements are segregated. The two main fluid compartments are the intracellular and extracellular compartments. The intracellular compartment is the space within the organism's cells; it is separated from the extracellular compartment by cell membranes.

Maiken Nedergaard is a Danish neuroscientist most well known for discovering the glymphatic system. She is a jointly appointed professor in the Departments of Neuroscience and Neurology at the University of Rochester Medical Center. She holds a part-time appointment in the Department of Neurosurgery within the University of Rochester Center for Translational Neuromedicine, where she is the principal investigator of the Division of Glial Disease and Therapeutics laboratory. She is also Professor of Glial Cell Biology at the University of Copenhagen, Center for Translational Neuromedicine.

<span class="mw-page-title-main">Meningeal lymphatic vessels</span>

The meningeal lymphatic vessels are a network of conventional lymphatic vessels located parallel to the dural venous sinuses and middle meningeal arteries of the mammalian central nervous system (CNS). As a part of the lymphatic system, the meningeal lymphatics are responsible for draining immune cells, small molecules, and excess fluid from the CNS into the deep cervical lymph nodes. Cerebrospinal fluid and interstitial fluid are exchanged, and drained by the meningeal lymphatic vessels.

Steven A. Goldman is an American physician-scientist. His research focuses on the use of stem and progenitor cells for the treatment of neurodegenerative disorders such as Huntington's Disease, as well as for the treatment of glial diseases such as the pediatric leukodystrophies and multiple sclerosis.

The subarachnoid lymphatic-like membrane (SLYM) is a possible fourth meningeal layer that was proposed in 2023 in the brain of humans and mice.

Cellular extensions also known as cytoplasmic protrusions and cytoplasmic processes are those structures that project from different cells, in the body, or in other organisms. Many of the extensions are cytoplasmic protrusions such as the axon and dendrite of a neuron, known also as cytoplasmic processes.

References

↑ Bacyinski A, Xu M, Wang W, Hu J (2017). "The Paravascular Pathway for Brain Waste Clearance: Current Understanding, Significance and Controversy". Frontiers in Neuroanatomy. 11: 101. doi: 10.3389/fnana.2017.00101 . PMC 5681909 . PMID 29163074.
↑ Kiviniemi V, Wang X, Korhonen V, Keinänen T, Tuovinen T, Autio J, et al. (June 2016). "Ultra-fast magnetic resonance encephalography of physiological brain activity - Glymphatic pulsation mechanisms?". Journal of Cerebral Blood Flow and Metabolism. 36 (6): 1033–45. doi:10.1177/0271678X15622047. PMC 4908626 . PMID 26690495.
↑ Bohr T, Hjorth PG, Holst SC, Hrabětová S, Kiviniemi V, Lilius T, Lundgaard I, Mardal KA, Martens EA, Mori Y, Nägerl UV, Nicholson C, Tannenbaum A, Thomas JH, Tithof J, Benveniste H, Iliff JJ, Kelley DH, Nedergaard M (September 2022). "The glymphatic system: Current understanding and modeling". iScience. 25 (9): 104987. doi:10.1016/j.isci.2022.104987. PMC 9460186 . PMID 36093063.
↑ Konnikova M (11 January 2014). "Goodnight. Sleep Clean". The New York Times . Retrieved 18 February 2014. She called it the glymphatic system, a nod to its dependence on glial cells
1 2 3 Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, et al. (August 2012). "A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β". Science Translational Medicine. 4 (147): 147ra111. doi:10.1126/scitranslmed.3003748. PMC 3551275 . PMID 22896675.
1 2 Rennels ML, Gregory TF, Blaumanis OR, Fujimoto K, Grady PA (February 1985). "Evidence for a 'paravascular' fluid circulation in the mammalian central nervous system, provided by the rapid distribution of tracer protein throughout the brain from the subarachnoid space". Brain Research. 326 (1): 47–63. doi:10.1016/0006-8993(85)91383-6. PMID 3971148. S2CID 23583877.
↑ Takano T, Tian GF, Peng W, Lou N, Libionka W, Han X, Nedergaard M (February 2006). "Astrocyte-mediated control of cerebral blood flow". Nature Neuroscience. 9 (2): 260–7. doi:10.1038/nn1623. PMID 16388306. S2CID 6140428.
↑ Schummers J, Yu H, Sur M (June 2008). "Tuned responses of astrocytes and their influence on hemodynamic signals in the visual cortex". Science. 320 (5883): 1638–43. Bibcode:2008Sci...320.1638S. doi:10.1126/science.1156120. PMID 18566287. S2CID 16895889.
↑ Yuhas D (2012). "How the brain cleans itself". Nature. doi:10.1038/nature.2012.11216. ISSN 1476-4687. S2CID 183462941.
1 2 Amiry-Moghaddam M, Ottersen OP (December 2003). "The molecular basis of water transport in the brain". Nature Reviews. Neuroscience. 4 (12): 991–1001. doi:10.1038/nrn1252. PMID 14682361. S2CID 23975497.
↑ Verkman AS, Mitra AK (January 2000). "Structure and function of aquaporin water channels". American Journal of Physiology. Renal Physiology. 278 (1): F13-28. doi:10.1152/ajprenal.2000.278.1.F13. PMID 10644652.
1 2 Verkman AS, Binder DK, Bloch O, Auguste K, Papadopoulos MC (August 2006). "Three distinct roles of aquaporin-4 in brain function revealed by knockout mice". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1758 (8): 1085–93. doi: 10.1016/j.bbamem.2006.02.018 . PMID 16564496.
↑ Yool AJ (October 2007). "Aquaporins: multiple roles in the central nervous system". The Neuroscientist. 13 (5): 470–85. doi:10.1177/1073858407303081. PMID 17901256. S2CID 46231509.
↑ Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, et al. (October 2013). "Sleep drives metabolite clearance from the adult brain". Science. 342 (6156): 373–7. Bibcode:2013Sci...342..373X. doi:10.1126/science.1241224. PMC 3880190 . PMID 24136970.
↑ Rangroo Thrane V, Thrane AS, Plog BA, Thiyagarajan M, Iliff JJ, Deane R, et al. (2013). "Paravascular microcirculation facilitates rapid lipid transport and astrocyte signaling in the brain". Scientific Reports. 3: 2582. Bibcode:2013NatSR...3E2582T. doi:10.1038/srep02582. PMC 3761080 . PMID 24002448.
↑ Mehler MF, Gokhan S (December 2000). "Mechanisms underlying neural cell death in neurodegenerative diseases: alterations of a developmentally-mediated cellular rheostat". Trends in Neurosciences. 23 (12): 599–605. doi:10.1016/s0166-2236(00)01705-7. PMID 11137149. S2CID 21302044.
↑ Narasimhan K (March 2006). "Quantifying motor neuron loss in ALS". Nature Neuroscience. 9 (3): 304. doi: 10.1038/nn0306-304 . PMID 16498424. S2CID 1933099.
↑ Gaberel T, Gakuba C, Goulay R, Martinez De Lizarrondo S, Hanouz JL, Emery E, et al. (October 2014). "Impaired glymphatic perfusion after strokes revealed by contrast-enhanced MRI: a new target for fibrinolysis?". Stroke. 45 (10): 3092–6. doi: 10.1161/STROKEAHA.114.006617 . PMID 25190438.
↑ Ng Kee Kwong KC, Mehta AR, Nedergaard M, Chandran S (August 2020). "Defining novel functions for cerebrospinal fluid in ALS pathophysiology". Review. Acta Neuropathologica Communications. 8 (1): 140. doi: 10.1186/s40478-020-01018-0 . PMC 7439665 . PMID 32819425.
1 2 3 Hajdu S (2003). "A Note from History: Discovery of the Cerebrospinal Fluid" (PDF). Annals of Clinical and Laboratory Science. 33 (3).
1 2 3 4 Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, et al. (July 2015). "Structural and functional features of central nervous system lymphatic vessels". Nature. 523 (7560): 337–41. Bibcode:2015Natur.523..337L. doi:10.1038/nature14432. PMC 4506234 . PMID 26030524.
1 2 Aspelund A, Antila S, Proulx ST, Karlsen TV, Karaman S, Detmar M, et al. (June 2015). "A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules". The Journal of Experimental Medicine. 212 (7): 991–9. doi:10.1084/jem.20142290. PMC 4493418 . PMID 26077718.
↑ Abbott NJ, Pizzo ME, Preston JE, Janigro D, Thorne RG (March 2018). "The role of brain barriers in fluid movement in the CNS: is there a 'glymphatic' system?". Acta Neuropathologica. 135 (3): 387–407. doi: 10.1007/s00401-018-1812-4 . PMID 29428972.
↑ Abbott NJ (September 2004). "Evidence for bulk flow of brain interstitial fluid: significance for physiology and pathology". Neurochemistry International. 45 (4): 545–52. doi:10.1016/j.neuint.2003.11.006. PMID 15186921. S2CID 10441695.
↑ Bradbury MW, Cserr HF, Westrop RJ (April 1981). "Drainage of cerebral interstitial fluid into deep cervical lymph of the rabbit". The American Journal of Physiology. 240 (4): F329-36. doi:10.1152/ajprenal.1981.240.4.F329. PMID 7223890.
1 2 Cserr HF (April 1971). "Physiology of the choroid plexus". Physiological Reviews. 51 (2): 273–311. doi:10.1152/physrev.1971.51.2.273. PMID 4930496.
↑ Nicholson C, Phillips JM (December 1981). "Ion diffusion modified by tortuosity and volume fraction in the extracellular microenvironment of the rat cerebellum". The Journal of Physiology. 321: 225–57. doi:10.1113/jphysiol.1981.sp013981. PMC 1249623 . PMID 7338810.
1 2 Cserr HF, Cooper DN, Suri PK, Patlak CS (April 1981). "Efflux of radiolabeled polyethylene glycols and albumin from rat brain". The American Journal of Physiology. 240 (4): F319-28. doi:10.1152/ajprenal.1981.240.4.F319. PMID 7223889.
↑ Rennels ML, Blaumanis OR, Grady PA (1990). "Rapid solute transport throughout the brain via paravascular fluid pathways". Advances in Neurology. 52: 431–9. PMID 2396537.
↑ Pullen RG, DePasquale M, Cserr HF (September 1987). "Bulk flow of cerebrospinal fluid into brain in response to acute hyperosmolality". The American Journal of Physiology. 253 (3 Pt 2): F538-45. doi:10.1152/ajprenal.1987.253.3.F538. PMID 3115117.