The formation of cerebrospinal fluid: Nearly a hundred years of interpretations and misinterpretations

The first scientific and experimental approaches to the study of cerebrospinal fluid (CSF) formation began almost a hundred years ago. Despite researchers being interested for so long, some aspects of CSF formation are still insufficiently understood. Today it is generally believed that CSF formation is an active energy consuming metabolic process which occurs mainly in brain ventricles, in choroid plexuses. CSF formation, together with CSF absorption and circulation, represents the so-called classic hypothesis of CSF hydrodynamics. In spite of the general acceptance of this hypothesis, there is a considerable series of experimental results that do not support the idea of the active nature of CSF formation and the idea that choroid plexuses inside the brain ventricles are the main places of formation. The main goal of this review is to summarize the present understanding of CSF formation and compare this understanding to contradictory experimental results that have been obtained so far. And finally, to try to offer a physiological explanation by which these contradictions could be avoided. We therefore analyzed the main methods that study CSF formation, which enabled such an understanding, and presented their shortcomings, which could also be a reason for the erroneous interpretation of the obtained results. A recent method of direct aqueductal determination of CSF formation is shown in more detail. On the one hand, it provides the possibility of direct insight into CSF formation, and on the other, it clearly indicates that there is no net CSF formation inside the brain ventricles. These results are contradictory to the classic hypothesis and, together with other mentioned contradictory results, strongly support a recently proposed new working hypothesis on the hydrodynamics of CSF. According to this new working hypothesis, CSF is permanently produced and absorbed in the whole CSF system as a consequence of filtration and reabsorption of water volume through the capillary walls into the surrounding brain tissue. The CSF exchange between the entire CSF system and the surrounding tissue depends on (patho)physiological conditions that predominate within those compartments.     

Reassessment of the pathways responsible for cerebrospinal fluid absorption in the neonate

Objective In neonatal lambs, the quantitative evidence suggests that a significant volume of cranial CSF drainage is associated with transport along olfactory nerves with absorption primarily into extracranial lymphatics in the paranasal region. Arachnoid granulations appear to be poorly developed at this level of development and their function is unknown. In this report, we tested whether a CSF protein tracer (¹³¹I-human serum albumin) could transport directly into the superior sagittal sinus of newborn lambs.Methods and results The concentration of the tracer administered into the CSF compartment was measured in the confluence of the intracranial venous sinuses (torcula) and in the peripheral blood (inferior vena cava). Enrichment of the CSF tracer in the cranial venous system was most evident when the CSF-venous sinus pressure gradients approached 20–30 cm H₂O.Conclusion The data suggests that neonatal CSF can be absorbed directly into the cranial venous system. However, contrary to the classical view, this route may represent an auxiliary system that is recruited to compliment lymphatic transport when intracranial pressures are very high.     

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

The protein tracer, horseradish peroxidase (HRP), was infused into the lateral cerebral ventricles or subarachnoid space of anesthetized cats and dogs after insertion of a cisternal cannula to permit drainage of cerebrospinal fluid (CSF) and tracer solution. The intracerebral distribution of the tracer was then determined by light microscopy of serial brain sections after postinfusion intervals of 4 min-2 h. For the localization of HRP, sections were incubated with diaminobenzidine (DAB) or the much more sensitive chromogen, tetramethylbenzidine (TMB). The TMB reaction showed a consistent 'paravascular' distribution of tracer reaction product, within the perivascular spaces (PVS) around large penetrating vessels and in the basal laminae around capillaries, far beyond the termination of the PVS. After infusion of HRP over 4 min, arterioles were surrounded by the tracer, but capillaries and venules were usually less densely demarcated; by 6 min, however, the intraparenchymal microvasculature was outlined in toto throughout the forebrain and brainstem. Electron microscopy of sections incubated in DAB after 10 or 20 min HRP circulation confirmed the paravascular location of the reaction product, which was also dispersed throughout the extracellular spaces (ECS) of the adjacent parenchyma. Our results demonstrate that solutes in the CSF have access to the ECS throughout the neuraxis within minutes via fluid pathways paralleling the intraparenchymal vasculature. The rapid paravascular influx of HRP could be prevented by stopping or diminishing the pulsations of the cerebral arteries by aortic occlusion or by partial ligation of the brachiocephalic artery. The exchange of solutes between the CSF and the cerebral ECS has generally been attributed to diffusion, however, HRP enters the neuraxis along the intraparenchymal microvasculature far more rapidly than can be explained on this basis. This apparent convective tracer influx may be facilitated by transmission of the pulsations of the cerebral arteries to the microvasculature. We postulate that a fluid circulation through the CNS occurs via paravascular pathways.     

Hydrocephalus: is impaired cerebrospinal fluid circulation only one problem involved?

Hydrocephalus is a complex disease of the brain as a whole, and imbalance between cerebrospinal fluid (CSF) formation and absorption is not the sole mechanism involved in its pathophysiology. In the absence of a lymphatic system in the central nervous system, open communication between CSF and interstitial fluid (ISF) of the brain may contribute to maintaining homeostasis of the brain, keeping the microchemical environment in good balance. Membranes or cell layers separating CSF from ISF of the brain do not provide impermeability, so the CSF communicates with ISF across the ependymal layer and the pial surface of the brain. In contradiction of the classical theory, the CSF one may obtain at the cisterna magna, for instance, is different from the newly formed CSF out of the choroid plexus, because it has been modified by the free communication between CSF and ISF spaces as the CSF descends along the neural axis. Free flow of water and some smaller molecules provides a bidirectional movement of water and other materials, and this must play an important role in brain volume control. The significance of this role should not be overlooked in regard to the pathophysiology of hydrocephalus.     

Classification of the cerebral edemas with reference to hydrocephalus and pseudotumor cerebri

Cerebral edema is a common clinical disorder that results from an abnormal increase in water content within the extracellular (EC) compartment of the brain. It is distinguished from two other types of brain bulk enlargement: (1) vascular swelling, caused by arterial dilatation or venous obstruction; and (2) cellular swelling, caused by cytotoxic injuries or metabolic storage. Under normal conditions, the EC compartment has two fluids, the interstitial fluid (ISF) and the cerebrospinal fluid (CSF), and extends from the blood brain barrier (BBB) through a series of 100 to 150-Å-wide intercellular spaces that are anatomically continuous with the CSF spaces. There are four primary types of EC edema: (1) vasogenic edema, which results from an increase in brain capillary permeability, the most common type, in which leakage of plasma constituents into the brain follows the pathways of ISF bulk flow and is governed by the interaction of systemic arterial pressure and tissue resistance; (2) osmotic edema, which results from an unfavorable osmotic gradient between the plasma and ISF across an intact BBB; (3) compressive edema, which results from obstruction of ISF bulk flow pathways; and (4) hydrocephalic edema, which results from obstruction of CSF bulk flow pathways. In this latter type of edema, distension of the collecting channels proximal to the block leads to retrograde flooding of the EC compartment with the formation of periventricular edema. The syndrome of pseudotumor cerebri includes several different types of brain bulk enlargement.     

The effect of increased CSF pressure on interstitial fluid flow during ventriculocisternal perfusion in the cat

Transependymal absorption of cerebrospinal fluid (CSF) in hydrocephalus is suggested by periventricular edema, but the necessary bulk flow of interstitial fluid (ISF) has not been found. We performed ventriculocisternal perfusions in adult cats using CSF with the extracellular marker [³H]sucrose. CSF pressure was maintained at — 5 (control), 20 or 40 cm H₂O for 2 or 4 h. Some animals had perfusions with isotope for the full experiment while others had an isotope-free perfusion for 2 h followed by a delayed-pulse with isotope. Apparent diffusion coefficients and distribution spaces for sucrose were determined from depth of isotope penetration. White matter apparent diffusion coefficients were statistically increased compared to controls for the 4-h 20 cm H₂O and 2-h 40 cm H₂O experiments. Apparent diffusion coefficients for delayed-pulse experiments at increased pressure were greater than those of full-pulse. Sucrose distribution spaces were not enlarged at the various pressures. Alteration of ISF transport in periventricular white matter occurred with increased pressure. These time-dependent changes in bulk flow rate indicate either a decrease in normal ISF flow toward the ventricle or reversal of transependymal ISF flow.     

The peripheral cerebrospinal fluid outflow pathway – physiology and pathophysiology of CSF recirculation: A review and hypothesis

An anatomical connection from subarachnoid spaces along nerves into peripheral tissues represents an important route for CNS antigens release, termed here peripheral cerebrospinal fluid outflow pathway (PCOP), is assumed analogous to mammals in humans: CSF leaves the subarachnoid spaces along nerves and joins respective interstitial tissue fluids, then the lymph then blood; in detail, flowing from the subfrontal subarachnoid spaces through the cribriform plate near olfactory nerves to nasal submucosa to the cervical lymph system, along cranial nerves and spinal nerves into respective peripheral tissues. Microanatomic details and relative shares of outflow volumes at various parts of the PCOP as compared to CSF reabsorption volumes into the venous system remain to be determined.Beyond, CSF functions as a third signaling system involving all CNS structures preferably surfaces, including spinal cord and nerve roots. But CSF may interact also with all cranial and peripheral nerves via the PCOP, and related peripheral tissues connected by nerves, e.g. subcutaneous tissues, muscles or neuronal ganglia, and even, a special case, the eye. PCOP associated pathomechanisms might arise with any abnormal pathogenic CSF contents including solutes and cells in various diseases, relevant especially in acute neuroinflammation, possibly in systemic inflammation, likely in chronic neuroinflammation and possibly in low level neuroinflammation. The latter may include subgroups of psychiatric disorders. PCOP associated pathomechanisms might explain for example the surprising muscle involvement in depression and schizophrenia, or diffuse pain or dysautonomia. PCOP associated pathomechanisms should generally relate to PCOP anatomy and the CSF outflow physiology respectively pathophysiology.     

CSF drains directly from the subarachnoid space into nasal lymphatics in the rat. Anatomy, histology and immunological significance

Cerebrospinal fluid (CSF) drainage pathways from the rat brain were investigated by the injection of 50 μl Indian ink into the cisterna magna. The distribution of the ink, as it escaped from the cranial CSF space, was documented in 2 mm thick slices of brain and skull cleared in cedar wood oil and in decalcified paraffin sections. Following injection of the ink, deep cervical lymph nodes were selectively blackened within 30 min and lumbar para-aortic nodes within 6 h. Within the cranial cavity, carbon particles accumulated in the basal cisterns but were also distributed in the paravascular spaces around the middle cerebral arteries and the nasal-olfactory artery. Carbon particles in the subarachnoid space beneath the olfactory bulbs drained directly into discrete channels which passed through the cribriform plate and into lymphatics in the nasal submucosa. Although ink was distributed along the subarachnoid space of the optic nerves and entered the cochlea, the nasal route was the only direct connection between cranial CSF and lymphatics. Arachnoid villi associated with superior and inferior sagittal sinuses were identified and a minor amount of drainage of ink into dural lymphatics was also observed. This study demonstrates the direct drainage of cerebrospinal fluid through the cribriform plate in anatomically defined channels which connect with the nasal lymphatics. Such a pathway is compatible with the observed rapidity of the bulk flow drainage of CSF in the rat, accords with the known specificity of immunological reactions to antigens injected into brain tissue, and may also serve as a route for drainage for lymphocytes and macrophages from the brain to the regional cervical lymph nodes.     

脑脊液内细胞移植治疗脊髓损伤

经脑脊液进行细胞移植治疗脊髓损伤具有较大的临床应用前景.有关研究显示,经脑脊液进行的细胞移植方法安全、方便,对病人的损伤小,适用于治疗中枢神经系统多发疾病.但是经脑脊液移植的细胞能否促进中枢神经系统轴突再生和脊髓神经功能修复仍存在争议,其作用机制、移植时间以及移植细胞种类方面还需要进一步研究.本文对经脑脊液细胞移植方法用于治疗脊髓损伤进行综述,探讨此方法对脊髓损伤后中枢神经系统内轴突再生及功能修复的促进作用.     

Paradigm shift in hydrocephalus research in legacy of Dandy’s pioneering work: rationale for third ventriculostomy in communicating hydrocephalus

Objective This study aims to question the generally accepted cerebrospinal fluid (CSF) bulk flow theory suggesting that the CSF is exclusively absorbed by the arachnoid villi and that the cause of hydrocephalus is a CSF absorption deficit. In addition, this study aims to briefly describe the new hydrodynamic concept of hydrocephalus and the rationale for endoscopic third ventriculostomy (ETV) in communicating hydrocephalus. Critique The bulk flow theory has proven incapable of explaining the pivotal mechanisms behind communicating hydrocephalus. Thus, the theory is unable to explain why the ventricles enlarge, why the CSF pressure remains normal and why some patients improve after ETV. Hydrodynamic concept of hydrocephalus Communicating hydrocephalus is caused by decreased intracranial compliance increasing the systolic pressure transmission into the brain parenchyma. The increased systolic pressure in the brain distends the brain towards the skull and simultaneously compresses the periventricular region of the brain against the ventricles. The final result is the predominant enlargement of the ventricles and narrowing of the subarachnoid space. The ETV reduces the increased systolic pressure in the brain simply by venting ventricular CSF through the stoma. The patent aqueduct in communicating hydrocephalus is too narrow to vent the CSF sufficiently.     

Superparamagnetic beads for estimation of spinal subarachnoid space permeability in rats

Background

Human spinal pathological processes have been linked to a loss of spinal subarachnoid space (SSAS) permeability, which has therefore become a target for therapy. Hence, it has become important to measure SSAS patency in rat models of these human disorders.

New method

The estimation of in vivo rat SSAS patency is described by quantifying passage of streptavidin-covered superparamagnetic beads (SPMB) in cerebrospinal fluid (CSF). Beads are injected into the cisterna magna and recovered at spinal level L2. They are then coated with biotynilated horseradish peroxidase for enzymatically based colorimetric measurement, after removal of bloody CSF to avoid interference with the colorimetric readings. The procedure was tested in intact rats and in rats 24 h after T9 laminectomy. Residual beads in SSAS were viewed by histology.

Results

Average bead recovery from intact rats was 6.4% of amount initially administered, in a mean CSF volume of 126 μL; in laminectomized rats, it was 1%, in a mean CSF volume of 39.2 μL.

Comparison with existing method(s)

Unlike in vivo imaging techniques, such as myelography (used here to validate our method) and near infrared fluorescence technology for qualitative rat SSAS patency viewing, our SPMB-based method allows for an in vivo quantitative estimation of the permeability of this space.

Conclusions

A novel method has been established to reliably determine SSAS permeability in rats. The method is reproducible and has the required sensitivity to detect an 84.4% reduction in bead recovery, as seen in laminectomized rats compared to intact animals.     

Subarachnoid injection of Microfil reveals connections between cerebrospinal fluid and nasal lymphatics in the non-human primate

Based on quantitative and qualitative studies in a variety of mammalian species, it would appear that a significant portion of cerebrospinal fluid (CSF) drainage is associated with transport along cranial and spinal nerves with absorption taking place into lymphatic vessels external to the central nervous system. CSF appears to convect primarily through the cribriform plate into lymphatics associated with the submucosa of the olfactory and respiratory epithelium. However, the significance of this pathway for CSF absorption in primates has never been established unequivocally. In past studies, we infused Microfil into the subarachnoid compartment of numerous species to visualize CSF transport pathways. The success of this method encouraged us to use a similar approach in the non-human primate. Yellow Microfil was injected post mortem into the cisterna magna of 6 years old Barbados green monkeys (Cercopithecus aethiops sabeus, n = 6). Macroscopic and microscopic examination revealed that Microfil was (1) distributed throughout the subarachnoid compartment, (2) located in the perineurial spaces associated with the fila olfactoria, (3) present within the olfactory submucosa, and (4) situated within an extensive network of lymphatic vessels in the nasal submucosa, nasal septum and turbinate tissues. We conclude that the Microfil distribution patterns in the monkey were very similar to those observed in many other species suggesting that significant nasal lymphatic uptake of CSF occurs in the non-human primate.     

Directional and compartmentalised drainage of interstitial fluid and cerebrospinal fluid from the rat brain

Summary Pathways for drainage of interstitial fluid and cerebrospinal fluid from the rat brain were investigated by the injection of 2–5 l Indian ink into cerebral white and grey matter and into the subarachnoid space over the vertex of the left frontal lobe. Animals were killed by formalin or glutaraldehyde perfusion 5 min-2 years after injection, and the distribution of ink over the surface of the brain, in 2-mm slices of brain cleared in cedar wood oil, in paraffin sections and by electron microscopy was documented. These investigations showed that carbon particles were distributed diffusely through the interstitial spaces of the white matter whereas they spread selectively along perivascular spaces in the grey matter outlining both arteries and veins and extending to surround capillaries within 1 h. Carbon particles were rapidly ingested by perivascular cells and, to some extent, by meningeal cells surrounding the larger vessels. Very little movement of carbon-labelled perivascular cells and perivascular macrophages was seen after 2 years. Carbon particles entering the subarachnoid space over the vertex of the cerebral hemispheres drained along selected paravascular and subfrontal pathways in the subarachnoid space to the cribriform plate and thence into nasal lymphatics and cervical lymph nodes. These studies demonstrate the diffuse spread of fluidborne tracers through cerebral white matter in the rat, the perivascular spread of tracer in grey matter and the compartmentalised directional flow or tracer through the subarachnoid space to the cribriform plate and nasal lymphatics. Furthermore, particulate matter selectively injected into perivascular spaces in rat grey matter is rapidly and efficiently ingested by perivascular cells.E. T. Z. supported by the James Gibson Fund, the Wessex Medical Trust, the Wessex Neurological Centre Research Trust, and the Sino-British Society     

Loss of perivascular aquaporin-4 in idiopathic normal pressure hydrocephalus

Idiopathic normal pressure hydrocephalus (iNPH) is a subtype of dementia that may be successfully treated with cerebrospinal fluid (CSF) diversion. Recently, magnetic resonance imaging (MRI) using a MRI contrast agent as a CSF tracer revealed impaired clearance of the CSF tracer from various brain regions such as the entorhinal cortex of iNPH patients. Hampered clearance of waste solutes, for example, soluble amyloid-β, may underlie neurodegeneration and dementia in iNPH. The goal of the present study was to explore whether iNPH is associated with altered subcellular distribution of aquaporin-4 (AQP4) water channels, which is reported to facilitate CSF circulation and paravascular glymphatic drainage of metabolites from the brain parenchyma. Cortical brain biopsies of 30 iNPH patients and 12 reference individuals were subjected to AQP4 immunogold cytochemistry. Electron microscopy revealed significantly reduced density of AQP4 water channels in astrocytic endfoot membranes along cortical microvessels in patients with iNPH versus reference subjects. There was a significant positive correlation between density of AQP4 toward endothelial cells (perivascular) and toward parenchyma, but the reduced density of AQP4 toward parenchyma was not significant in iNPH. We conclude that perivascular AQP4 expression is attenuated in iNPH, potentially contributing to impaired glymphatic circulation, and waste clearance, and subsequent neurodegeneration. Hence, restoring normal perivascular AQP4 distribution may emerge as a novel treatment strategy for iNPH.     

Lymphatic drainage of the brain and the pathophysiology of neurological disease

There are no conventional lymphatics in the brain but physiological studies have revealed a substantial and immunologically significant lymphatic drainage from brain to cervical lymph nodes. Cerebrospinal fluid drains via the cribriform plate and nasal mucosa to cervical lymph nodes in rats and sheep and to a lesser extent in humans. More significant for a range of human neurological disorders is the lymphatic drainage of interstitial fluid (ISF) and solutes from brain parenchyma along capillary and artery walls. Tracers injected into grey matter, drain out of the brain along basement membranes in the walls of capillaries and cerebral arteries. Lymphatic drainage of antigens from the brain by this route may play a significant role in the immune response in virus infections, experimental autoimmune encephalomyelitis and multiple sclerosis. Neither antigen-presenting cells nor lymphocytes drain to lymph nodes by the perivascular route and this may be a factor in immunological privilege of the brain. Vessel pulsations appear to be the driving force for the lymphatic drainage along artery walls, and as vessels stiffen with age, amyloid peptides deposit in the drainage pathways as cerebral amyloid angiopathy (CAA). Blockage of lymphatic drainage of ISF and solutes from the brain by CAA may result in loss of homeostasis of the neuronal environment that may contribute to neuronal malfunction and dementia. Facilitating perivascular lymphatic drainage of amyloid-β (Aβ) in the elderly may prevent the accumulation of Aβ in the brain, maintain homeostasis and provide a therapeutic strategy to help avert cognitive decline in Alzheimer’s disease.     

Physiological and biochemical principles underlying volume-targeted therapy—The “lund concept”

The optimal therapy of sustained increase in intracranial pressure (ICP) remains controversial. The volume-targeted therapy (“Lund concept”) discussed in this article focuses on the physiological volume regulation of the intracranial compartments. The balance between effective transcapillary hydrostatic and osmotic pressures constitutes the driving force for transcapillary fluid exchange. The low permeability for sodium and chloride combined with the high crystalloid osmotic pressure (approximately 5700 mmHg) on both sides of the blood-brain barrier (BBB) counteracts fluid exchange across the intact BBB. Additionally, variations in systemic blood pressure generally are not transmitted to these capillaries because cerebral intracapillary hydrostatic pressure (and blood flow) is physiologically tightly autoregulated. Under pathophysiological conditions, the BBB may be partially disrupted. Transcapillary water exchange is then determined by the differences in hydrostatic and colloid osmotic pressure between the intra- and extracapillary compartments. Pressure autoregulation of cerebral blood flow is likely to be impaired in these conditions. A high cerebral perfusion pressure accordingly increases intracapillary hydrostatic pressure and leads to increased intracerebral water content and an increase in ICP. The volume-targeted “Lund concept” has been evaluated in experimental and clinical studies to examine the physiological and biochemical (utilizing intracerebral microdialysis) effects, and the clinical experiences have been favorable.     

Penetration and removal of horseradish peroxidase injected into the cerebrospinal fluid: Role of cerebral perivascular spaces,endothelium and microglia

Summary The distribution of horseradish peroxidase (HRP) in hypothalamic and cortical brain tissues was studied at different time intervals after injection into the lateral ventricle of adult Wistar rats. A preferential penetration of the tracer was found along the perivascular spaces of blood vessels. Their importance for the exchange between CSF and extracellular space of the brain is discussed. It is suggested that the preferential penetration route extends beyond the range of the Virchow-Robin space down to the level of the capillaries.Although the intercellular clefts between endothelial cells are sealed by tight junctions there is a retrograde vesicular transport of the tracer to the blood stream which contributes to the removal of HRP from the brain tissue. This indicates that in this case one has to distinguish between a blood-brain barrier and a brain-blood barrier.One of the main factors in the removal and degradation of the foreign protein is shown to be the perivascular microglia the identity of which is readily established by comparing its appearance in the light and electron microscope.     

The effects of chronic serum sickness on albumin distribution and glucose utilization in rat brain

Summary The level of cerebrospinal fluid (CSF) protein is elevated in diseases and disease models that are associated with circulating immune complexes such as serum sickness. Circulatory immune complexes are known to deposit in the basal lamina of fenestrated capillaries and may, as a result, affect both capillary bed and parenchymal function. Since the brain has both fenestrated and unfenestrated capillaries and immune complexes deposit to a varying extent in the fenestrated capillaries in chronic serum sickness, cerebral capillary permeability to protein may be altered in some brain areas and lead to the elevation of CSF proteins. In addition various other cerebrovascular and metabolic functions may also be affected by this condition. In this study either radio-iodinated serum albumin (RISA) or 2-[¹⁴C]deoxyglucose (¹⁴C-2DG) was intravenously injected into control Wistar rats and Wistar rats with chronic serum sickness; subsequently the tissue levels of radioactivity were measured by quantitative autoradiography in 4 brain areas with fenestrated capillaries and 11 brain areas with unfenestrated capillaries. The 2-min distribution of RISA, which demarcates the volume of circulating plasma in perfused microvessels and is generally proportional to local plasma flow, was the same in control and experimental rats. The passage of RISA from blood into brain over 30 min was negligible in both groups; thus cerebral capillary permeability to albumin was not detectably increased in any of these 15 brain areas by chronic serum sickness. The rate of local cerebral glucose utilization, an indicator of local metabolic and neural activity, was calculated from the ¹⁴C-2DG data and was virtually identical in control and experimental rats. These results suggest that chronic serum sickness at this stage has little effect on capillary bed permeability and parenchymal function in most, if not all, brain areas.Supported by NIH Grant NS 21157 and VA Merit Funding     

The Glymphatic System: A Novel Component of Fundamental Neurobiology

Throughout the body, lymphatic fluid movement supports critical functions including clearance of excess fluid and metabolic waste. The glymphatic system is the analog of the lymphatic system in the CNS. As such, the glymphatic system plays a key role in regulating directional interstitial fluid movement, waste clearance, and, potentially, brain immunity. The glymphatic system enables bulk movement of CSF from the subarachnoid space along periarterial spaces, where it mixes with interstitial fluid within the parenchyma before ultimately exiting from the parenchyma via perivenous spaces. This review focuses on important questions about the structure of this system, why the brain needs a fluid transport system, and unexplored aspects of brain fluid transport. We provide evidence that astrocytes and blood vessels determine the shape of the perivascular space, ultimately controlling the movement of perivascular fluid. Glymphatic fluid movement has the potential to alter local as well as global transport of signaling molecules and metabolites. We also highlight the evidence for cross talk among the glymphatic system, cardiovascular system, gastrointestinal tract, and lymphatic system. Much remains to be studied, but we propose that the glymphatic/lymphatic system acts as a cornerstone in signaling between the brain and body.     

Intracisternal enzyme replacement therapy in lysosomal storage diseases: routes of absorption into brain

R. D. Jolly, N. R. Marshall, M. R. Perrott, K. E. Dittmer, K. M. Hemsley and H. Beard (2011) Neuropathology and Applied Neurobiology 37, 414–422
Intracisternal enzyme replacement therapy in lysosomal storage diseases: routes of absorption into brain Aims: The research concerns enzyme replacement therapy in lysosomal storage diseases with central nervous system involvement. The principle aim was to understand the routes of entry of enzyme into the brain when delivered directly into the cerebrospinal fluid (CSF) via the cerebellomedullary cistern. Methods: Pathways for absorption of replacement enzyme were investigated in dogs with mucopolysaccharidosis IIIA (MPSIIIA) following intracisternal injections of human recombinant N‐sulphoglucosamine sulphohydrolase (rhSGSH, EC3.10.1.1) by light and confocal microscopy using chromogenic and fluorescent immune probes. Results: Enzyme entered the brain superficially by penetration of the pia/glia limitans interface, but the main route was perivascular along large veins, arteries and arterioles extending onto capillaries. It further dispersed into surrounding neuropil to be taken up by neurones, macrophages, astrocytes and oligodendroglia. Enzyme also entered the lateral ventricles adjacent to the choroid plexus, probably also by the tela choroidea and medullary velum, with further spread throughout the ventricular system and spinal canal. There was secondary spread back across the ependyma into nervous tissue of brain and spinal cord. Conclusions: Enzyme mainly enters the brain by a perivascular route involving both arteries and veins with subsequent spread within the neuropil from where it is taken up by a proportion of neurones and other cells. Penetration of enzyme through the pia/glia limitans is minor and superficial.