The meninges as barriers and facilitators for the movement of fluid, cells and pathogens related to the rodent and human CNS.

“Since the arachnoid blood–CSF barrier is avascular and provides a relatively small surface area, it is generally considered that it does not contribute significantly to blood–brain exchange [1].”

“The layers of leptomeningeal cells performing this barrier function are often only one cell thick and joined by gap junctions or desmosomes [4, 13].”

“…stages have been translated according to the revision by O’Rahilly and Müller [71] and from mammals to human according to the work of Clancy et al. [22] E14 etc. embryonic day Schmechel and Rakic [86]; Voigt [101] 25th–28th Transition from subpial end feet layer to glia limitans Human Kadhim et…”

“Another route of entry of T cells into the CSF appears to be through the choroid plexus and blood CSF barrier into the ventricles [78].”

“Four major molecular subgroups of medulloblastoma have been recognised: wingless (WNT), sonic hedgehog (SHH), group 3 and group 4 [77] but whole genome landscapes have revealed additional new molecular subtypes [69].”

“Although veins in the SAS are coated by a layer of leptomeningeal cells, the main barrier to entry of inflammatory cells from the blood into the CSF in the SAS is the vascular endothelium lining veins in the SAS and subpial spaces [30, 31].”

“12 (13th–15th) Radial glial cells begin to transform into astrocytes Rhesus monkey (E64) and newborn ferret Schmechel and Rakic [86]; Voigt [101]”

“The probability of direct efflux of tracer into the CSF following injection into the brain through too large a needle in too great a volume was identified by Carare et al. [17].”

“…that leptomeninges play a facilitating role in fluid balance between CSF and interstitial fluid within the CNS. Convective flow of CSF and interstitial fluid through the brain parenchyma driven by aquaporin 4 as suggested by the “glymphatic” hypothesis [46] has been strongly contested [2, 91].”

“12 (13th–15th) Radial glial cells begin to transform into astrocytes Rhesus monkey (E64) and newborn ferret Schmechel and Rakic [86]; Voigt [101]”

“Channels lined by leptomeningeal cells form in the subarachnoid space under the olfactory bulbs and pass through the cribriform plate alongside olfactory nerves into the nasal submucosa [54].”

“In the adult, an arachnoid blood–CSF barrier separates the fenestrated blood vessels in the dura from the CSF in the SAS by means of a cell layer joined by tight junctions (the arachnoid barrier layer) [65].”

“The tight junction protein, claudin-11, was initially described as the basis for the blood–testes barrier (Sertoli cell tight junctions) and shown to be the same as oligodendrocyte specific protein (OSP) responsible for the tight junctions between oligodendrocytic myelin sheaths and axons [63].”

“Results in Carnegie stages have been translated according to the revision by O’Rahilly and Müller [71] and from mammals to human according to the work of Clancy et al.”

“Encephalitogenic T cells also migrate across the walls of leptomeningeal veins directly into the CSF in the SAS [85].”

“Intracerebral injections of fluorescent tracers suggest that interstitial fluid and solutes drain rapidly out of the brain along basement membranes in the walls of capillaries and along basement membranes surrounding smooth muscle cells in the tunica media of cerebral arterioles and arteries [7, 16–18] [the Intramural…”

“The ability of meningococci to weaken endothelial and leptomeningeal intercellular junctions is a trafficking mechanism shared with T lymphocytes, B cells, PMNL and other myeloid cells for their entry into the CNS, and includes activation of MMP proteins [30].”

“Furthermore, the concept of the CSF as a sink for the drainage of ISF from the brain may need to be re-examined, particularly as the best estimate is that 85% of ISF from the brain drains to lymph nodes and only 15% of ISF passes into the CSF under normal conditions [94].”

“Most of the cisternae of the adult are already present Human O’Rahilly and Müller [70]”

“Meningococcal adherence to the endothelial cell barrier and the mechanism of traversal has been extensively studied [24].”

“Laminin receptor 1 (LamR; also known as RPSA)–galectin 3 (GAL3) complex) Binds PorA and PilQ [73] and NhhA (Neisseria hia/hsf homologue; Msf, meningococcal surface fibril) [84]”

“5b) [64] and by high-resolution confocal microscopy (Albargothy, Hawkes and Carare submitted paper) and not along periarteriolar “spaces”.”

“In this way arteries in the white matter differ from those in the cortex and the arrangement of leptomeningeal coats may be related to the capacity of the perivascular spaces around white matter arteries to dilate [79, 104].”

“…out of the brain along basement membranes in the walls of capillaries and along basement membranes surrounding smooth muscle cells in the tunica media of cerebral arterioles and arteries [7, 16–18] [the Intramural Peri-Arterial Drainage (IPAD) pathway]; IPAD is impaired with age in mice [40].”

“Leptomeningeal cells show variable ultrastructural and immunocytochemical characteristics depending upon the structures with which they are associated [4].”

“The inner layer of the arachnoid facing the CSF has a thin underlying layer of collagen that extends into trabeculae that cross the SAS to join the pia or suspend subarachnoid blood vessels within the SAS [4, 45].”

“Dilatation of perivascular spaces in the basal ganglia is related to age and small vessel disease and can be detected by MRI [38] and by histology [75].”

“Perivascular macrophages are embedded in the basement membranes that surround arteries and other blood vessels in the normal brain [37].”

“…out of the brain along basement membranes in the walls of capillaries and along basement membranes surrounding smooth muscle cells in the tunica media of cerebral arterioles and arteries [7, 16–18] [the Intramural Peri-Arterial Drainage (IPAD) pathway]; IPAD is impaired with age in mice [40].”

“Signalling leads to relocation of vascular endothelial cadherin from endothelial cell junctions at the sites of bacterial adherence, and also induces the production of MMP8 that promotes cleavage of the tight junction protein occludin [87].”

“Bind Opa proteins (which also recognise CEACAM (carcinoembryonic antigenrelated cell adhesion molecule) family receptor proteins) and Opc protein [42].”

“In this way arteries in the white matter differ from those in the cortex and the arrangement of leptomeningeal coats may be related to the capacity of the perivascular spaces around white matter arteries to dilate [79, 104].”

“Three major categories of tumours cause Meningeosis neoplastica: namely carcinomas, lymphomas and primary tumours of the CNS, particularly medulloblastomas [28, 77].”

“There is a series of dentate ligaments along the length of the human spinal cord that connect the dura to the substantial layer of subpial collagen encompassing the human spinal cord [68]; the dentate ligaments appear to stabilise the cord within the spinal SAS.”

“Intermediate layers of arachnoid within the spinal SAS are composed of a complex array of perforated sheets, mainly over the dorsal aspects of the spinal cord [68, 103]; these perforated sheets may play a role in regulating the flow of CSF within the spinal SAS.”

“Leptomeningeal cells also surround collagen bundles in the stroma of the choroid plexus [3] and in the cores of arachnoid granulations [56, 98].”

“Convective flow of CSF and interstitial fluid through the brain parenchyma driven by aquaporin 4 as suggested by the “glymphatic” hypothesis [46] has been strongly contested [2, 91].”

“Neutrophils with intracellular bacteria have been observed in the CSF of patients, suggesting that this organism can survive and replicate within these cells [25].”

“Expression of the Tfp-associated protein PilX stimulates bacterial aggregation and spreading across the cell surface [41].”

“The outer barriers of the brain function as morphogenetic signalling centres [27, 89], dynamic transport systems [108], a stem cell niche [27] and regulators of immune cell entry into the CNS [93] as summarised by Brøchner et al.”

“An additional sixth interface, (f) the interface between the CSF and the embryonic brain is present only in the foetus [62, 83].”

“1 3 inside choroidal epithelial cells or penetrating the tight junctions [76].”

“However in light of recent findings of drug transporters and drug-metabolising enzymes in the arachnoid blood–CSF barrier [108] and taking into account that the arachnoid barrier cell layer constitutes a much larger fraction of the brain surface area during early development, it is clear that the arachnoid blood–CSF b…”

“CSF then appears to pass by macrovacuolar bulk flow through the venous endothelium into the blood [97].”

“More recently it has been demonstrated that the early rat brain (E10–E14) shows no signs of claudin-11 immunoreactivity, but that at E15, weak staining is present in the loosely packed arachnoid barrier cells at the base of the brain and extending into the future tentorium cerebelli [14].”

“Laminin receptor 1 (LamR; also known as RPSA)–galectin 3 (GAL3) complex) Binds PorA and PilQ [73] and NhhA (Neisseria hia/hsf homologue; Msf, meningococcal surface fibril) [84]”

“However, during foetal life, CSF is not likely to drain through arachnoid granulations as they are not present prior to 39 weeks gestation [36].”

“LOS is the major component of meningococci that induces leptomeningitis [12], via binding to CD14-Toll-like receptor Fig.”

“Phosphoethanolamine modification of LOS can increase adherence to human cells and also protects meningococci from neutrophil extracellular trap (NET)-bound cathepsin G [58].”

“Leptomeningeal cells also surround collagen bundles in the stroma of the choroid plexus [3] and in the cores of arachnoid granulations [56, 98].”

“Dilated perivascular spaces around arteries in the human cerebral white matter can be detected by MRI and by histology and have been associated with CAA and consequent failure of drainage of interstitial fluid [19, 79, 104].”

“7c) [5, 9, 34, 39], although the nature of the bacterial ligands and meningeal cell receptors has not been explored extensively.”

“The outer barriers of the brain function as morphogenetic signalling centres [27, 89], dynamic transport systems [108], a stem cell niche [27] and regulators of immune cell entry into the CNS [93] as summarised by Brøchner et al.”

“Meningococci also avoid complement killing through expression of Porin A that binds the complement inhibitor C4 bp protein [47], and of fHbp (factor H binding protein), NspA (Neisserial surface protein A) and PorinB3, which all bind human factor H [35, 88].”

“Dilatation of perivascular spaces in the basal ganglia is related to age and small vessel disease and can be detected by MRI [38] and by histology [75].”

“…by O’Rahilly and Müller [71] and from mammals to human according to the work of Clancy et al. [22] E14 etc. embryonic day Schmechel and Rakic [86]; Voigt [101] 25th–28th Transition from subpial end feet layer to glia limitans Human Kadhim et al. [50] choroid plexus as this has not yet developed.”

“1 3 a very dense leptomeningeal vascular plexus, the vascular distribution system, in the SAS [62].”

“Other Tfp-associated proteins that may be involved in cell interactions include the tip-associated PilC1/C2 and a phosphorylcholine modification of Tfp that interacts with Platelet Activating Factor receptor [48].”

“They appear in greater number as children age and are clearly visible by 2 years and then increase further in size and number with increasing age [61].”

“Meningioma cells share many structural features with normal leptomeningeal cells [32]; they are characterised by the presence of desmosomes, and, except in certain sites in the leptomeninges, tight junctions are absent.”

“Only one other protein, the Adhesin Complex Protein, has been reported to bind directly to cell surfaces and mediate adherence of capsulated meningococci to meningeal cells [44].”

“In vitro and in vivo data suggest that expression of α9 and β1 integrins, in combination with tenascin in the extracellular matrix, mediate the adhesion of medulloblastoma cells to the leptomeninges [33].”

“By contrast, cytokine release by meningeal cells can occur independently of LOS-CD14/TLR4/MD2 interactions or the involvement of other host accessory proteins such as HSP70, HSP90α, CXCR4 or GDF5 [43].”

“7c) [5, 9, 34, 39], although the nature of the bacterial ligands and meningeal cell receptors has not been explored extensively.”

“Heparan sulphate proteoglycans (HSPG) Binds NhhA [84], NHBA (Neisseria Heparin Binding Antigen) [99], Opa and Opc proteins [42]”

“Binds to various meningococcal proteins (NMB0278, DsbA; NMB0346, NMB0667, NMB1513, hypothetical; NMB1220, Stomatin/Mec-2 family protein; NMB1567, Macrophage infectivity potentiator) [74]”

“The SAS is shallower and much less extensive in rodents than in humans [23, 54].”

“gonorrhoeae across polarised epithelial cells [29].”

“Meningococci also avoid complement killing through expression of Porin A that binds the complement inhibitor C4 bp protein [47], and of fHbp (factor H binding protein), NspA (Neisserial surface protein A) and PorinB3, which all bind human factor H [35, 88].”

“In endothelial cells, EGFR, Erb2 and Erb4 are activated in response to meningococcal infection and involved in the internalisation of bacteria [90].”

“Expression of TspA (T cell-stimulating protein A) has been reported to contribute to the adhesion of meningococci to meningioma cells [72].”

“For example, the α(2-8) N -acetyl-neuraminic acid linked homopolymer of serogroup B CPS is structurally identical to a modification of mammalian neural cell adhesion molecule (N-CAM) [95].”

“Histones Intracellular proteins that can associate with App (Adhesion and penetration autotransporter protein) and MspA/Aus1 (meningococcal serine protease A/autotransporter serine protease 1) [53]”

“7c) [5, 9, 34, 39], although the nature of the bacterial ligands and meningeal cell receptors has not been explored extensively.”

“It is predicted that molecular characterisation will lead to more targeted therapies for leptomeningeal metastases of medulloblastoma [67].”

“Complex barriers at the surface of the brain, particularly during development, are poorly defined [10], but by mid-gestation subarachnoid interfaces are almost fully developed.”

“The only regions of adherence are where cortical veins join venous sinuses in the dura and where a small number of vascular bundles containing arteries and veins cross the subarachnoid and subdural spaces from the surface of the brain to the dura [11].”

“Three major categories of tumours cause Meningeosis neoplastica : namely carcinomas, lymphomas and primary tumours of the CNS, particularly medulloblastomas [28, 77].”

“Interestingly, Tfp-mediated adherence of Neisseriae to the uropod of polarised PMNL suggests a hypothesis that the bacteria can hitchhike on PMNL both to hide from their phagocytic activity and to enable dissemination through cell barriers [92].”

“7c) [5, 9, 34, 39], although the nature of the bacterial ligands and meningeal cell receptors has not been explored extensively.”

“Arteriovenous malformations in the dura have a significant effect on the vasculature of the brain through these connections and may be associated with cerebral venous thrombosis or intracranial haemorrhage [82].”

“Much of the confusion has arisen first from artefact in histological and electron microscope preparations due to swelling of perivascular astrocytes thus forming an artefactual space around cortical arteries [81].”

“The leptomeningeal cells of the pia offer little resistance to the passage of inflammatory cells [45, 57] (Fig.”

“TLR2 Toll-like receptor 2: pathogen recognition receptor (PRR) for Grampositive lipoteichoic acid and other lipoproteins and meningococcal PorB [96]”

“There is one layer of leptomeningeal cells around arteries in the cerebral cortex but there tends to be two layers of leptomeninges surrounding arteries in the white matter and basal ganglia [26, 75, 109].”

“These findings are important in discussions about the continuity of the SAS and pial tissues with the stroma of the choroid plexus [107] and the so-called functional leak at the tela choroidea between ependyma and choroid plexus epithelium [13].”

“…out of the brain along basement membranes in the walls of capillaries and along basement membranes surrounding smooth muscle cells in the tunica media of cerebral arterioles and arteries [7, 16–18] [the Intramural Peri-Arterial Drainage (IPAD) pathway]; IPAD is impaired with age in mice [40].”

“Leptomeningitis is an acute, compartmentalised intracranial inflammatory response centred on the leptomeninges and can be caused by a plethora of different bacteria that can gain access to the SAS [20].”

“Leptomeningitis is an ‘inflammatory soup’ of host response molecules [21] to invading menin-gococci and infection is characterised by the rapid infiltration of PMNLs. Neutrophils with intracellular bacteria have been observed in the CSF of patients, suggesting that this organism can survive and…”

“Anatomical support for this pathway is found from developmental studies in rats that have indicated that the arachnoid barrier layer of the meninges is not present above the cribriform plate [146] and thus would not accompany the olfactory nerves outside of the skull.”