Top

Published in:

Open Access 01-03-2018 | Review

The role of brain barriers in fluid movement in the CNS: is there a ‘glymphatic’ system?

Authors: N. Joan Abbott, Michelle E. Pizzo, Jane E. Preston, Damir Janigro, Robert G. Thorne

Published in: Acta Neuropathologica | Issue 3/2018

Abstract

Brain fluids are rigidly regulated to provide stable environments for neuronal function, e.g., low K⁺, Ca²⁺, and protein to optimise signalling and minimise neurotoxicity. At the same time, neuronal and astroglial waste must be promptly removed. The interstitial fluid (ISF) of the brain tissue and the cerebrospinal fluid (CSF) bathing the CNS are integral to this homeostasis and the idea of a glia-lymph or ‘glymphatic’ system for waste clearance from brain has developed over the last 5 years. This links bulk (convective) flow of CSF into brain along the outside of penetrating arteries, glia-mediated convective transport of fluid and solutes through the brain extracellular space (ECS) involving the aquaporin-4 (AQP4) water channel, and finally delivery of fluid to venules for clearance along peri-venous spaces. However, recent evidence favours important amendments to the ‘glymphatic’ hypothesis, particularly concerning the role of glia and transfer of solutes within the ECS. This review discusses studies which question the role of AQP4 in ISF flow and the lack of evidence for its ability to transport solutes; summarizes attributes of brain ECS that strongly favour the diffusion of small and large molecules without ISF flow; discusses work on hydraulic conductivity and the nature of the extracellular matrix which may impede fluid movement; and reconsiders the roles of the perivascular space (PVS) in CSF–ISF exchange and drainage. We also consider the extent to which CSF–ISF exchange is possible and desirable, the impact of neuropathology on fluid drainage, and why using CSF as a proxy measure of brain components or drug delivery is problematic. We propose that new work and key historical studies both support the concept of a perivascular fluid system, whereby CSF enters the brain via PVS convective flow or dispersion along larger caliber arteries/arterioles, diffusion predominantly regulates CSF/ISF exchange at the level of the neurovascular unit associated with CNS microvessels, and, finally, a mixture of CSF/ISF/waste products is normally cleared along the PVS of venules/veins as well as other pathways; such a system may or may not constitute a true ‘circulation’, but, at the least, suggests a comprehensive re-evaluation of the previously proposed ‘glymphatic’ concepts in favour of a new system better taking into account basic cerebrovascular physiology and fluid transport considerations.

Definitions: ‘Peri’ is enclosing or surrounding (as in pericardial, perimeter); ‘Para’ has many, less specific meanings, along or beside, e.g. parathyroid—but this does not really apply to circumferential structures. In common terms, ‘para’ is alongside (as in paramedic) or relating to, not the structure enveloping something closely. So here we have chosen to use the term ‘perivascular’ for the small spaces surrounding vessels in which tracer can move, and this is also its most common usage for the BBB/NVU.

Abbott NJ (2004) Evidence for bulk flow of brain interstitial fluid: significance for physiology and pathology. Neurochem Int 45:545–552. https://doi.org/10.1016/j.neuint.2003.11.006 PubMedCrossRef

Abbott NJ (2013) Blood–brain barrier structure and function and the challenges for CNS drug delivery. J Inherit Metab Dis 36:437–449. https://doi.org/10.1007/s10545-013-9608-0 PubMedCrossRef

Abbott NJ, Rönnbäck L, Hansson E (2006) Astrocyte-endothelial interactions at the blood–brain barrier. Nat Rev Neurosci 7:41–53. https://doi.org/10.1038/nrn1824 PubMedCrossRef

Alcolado R, Weller RO, Parrish EP, Garrod D (1988) The cranial arachnoid and pia mater in man: anatomical and ultrastructural observations. Neuropathol Appl Neurobiol 14:1–17. https://doi.org/10.1111/j.1365-2990.1988.tb00862.x PubMedCrossRef

Ames A, Higashi K, Nesbett FB (1965) Relation of potassium concentration in choroidplexus fluid to that in plasma. J Physiol 181:506–515PubMedPubMedCentralCrossRef

Asgari M, de Zélicourt D, Kurtcuoglu V (2016) Glymphatic solute transport does not require bulk flow. Sci Rep 6:38635. https://doi.org/10.1038/srep38635 PubMedPubMedCentralCrossRef

Aspelund A, Antila S, Proulx ST, Karlsen TV, Karaman S, Detmar M, Wiig H, Alitalo K (2015) A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J Exp Med 212:991–999. https://doi.org/10.1084/jem.20142290 PubMedPubMedCentralCrossRef

Badaut J, Fukuda AM, Jullienne A, Petry KG (2014) Aquaporin and brain diseases. Biochim Biophys Acta Gen Subj 1840:1554–1565. https://doi.org/10.1016/j.bbagen.2013.10.032 CrossRef

Badaut J, Lasbennes F, Magistretti PJ, Regli L (2002) Aquaporins in brain: distribution, physiology, and pathophysiology. J Cereb Blood Flow Metab 22:367–378. https://doi.org/10.1097/00004647-200204000-00001 PubMedCrossRef

10.

Barkai A, Glusman M, Rapport MM (1972) Serotonin turnover in the intact cat brain. J Pharmacol Exp Ther 181:28–35PubMed

11.

Barresi R, Campbell KP (2006) Dystroglycan: from biosynthesis to pathogenesis of human disease. J Cell Sci 119:199–207. https://doi.org/10.1242/jcs.02814 PubMedCrossRef

12.

Bateman GA, Brown KM (2012) The measurement of CSF flow through the aqueduct in normal and hydrocephalic children: from where does it come, to where does it go? Childs Nerv Syst 28:55–63. https://doi.org/10.1007/s00381-011-1617-4 PubMedCrossRef

13.

Bauer HJ (1993) The Quincke centennial lecture. In: Felgenhauer K, Holzgraefe M, Prange H (eds) CNS barriers mod diagnostics. VCH, Weinheim, pp 27–32

14.

Borghammer P (2017) How does parkinson’s disease begin? Perspectives on neuroanatomical pathways, prions, and histology. Mov Disord. https://doi.org/10.1002/mds.27138

15.

Borlongan CV, Skinner SJM, Geaney M, Vasconcellos AV, Elliott RB, Emerich DF (2004) Intracerebral transplantation of porcine choroid plexus provides structural and functional neuroprotection in a rodent model of stroke. Stroke 35:2206–2210. https://doi.org/10.1161/01.STR.0000138954.25825.0b PubMedCrossRef

16.

Bradbury MW, Cserr HF, Westrop RJ (1981) Drainage of cerebral interstitial fluid into deep cervical lymph of the rabbit. Am J Physiol 240:F329–F336PubMed

17.

Bradbury MW, Westrop RJ (1983) Factors influencing exit of substances from cerebrospinal fluid into deep cervical lymph of the rabbit. J Physiol 339:519–534PubMedPubMedCentralCrossRef

18.

Brierley JB (1950) The penetration of particulate matter from the cerebrospinal fluid into the spinal ganglia, peripheral nerves, and perivascular spaces of the central nervous system. J Neurol Neurosurg Psychiatry 13:203–215PubMedPubMedCentralCrossRef

19.

Brightman MW (1968) The intracerebral movement of proteins injected into blood and cerebrospinal fluid of mice. Prog Brain Res 29:19–40. https://doi.org/10.1016/S0079-6123(08)64147-3 PubMedCrossRef

20.

Brightman MW (2002) The brain’s interstitial clefts and their glial walls. J Neurocytol 31:595–603PubMedCrossRef

21.

Brightman MW, Reese TS (1969) Junctions between intimately apposed cell membranes in the vertebrate brain. J Cell Biol 40:648–677. https://doi.org/10.1083/jcb.40.3.648 PubMedPubMedCentralCrossRef

22.

Brinker T, Stopa E, Morrison J, Klinge P (2014) A new look at cerebrospinal fluid circulation. Fluids Barriers CNS 11:10. https://doi.org/10.1186/2045-8118-11-10 PubMedPubMedCentralCrossRef

23.

Brown DA, Wijdicks EFM (2017) Decompressive craniectomy in acute brain injury. Crit Care Neurol Part I. https://doi.org/10.1016/b978-0-444-63600-3.00016-7

24.

Carare RO, Bernardes-Silva M, Newman TA, Page AM, Nicoll JAR, Perry VH, Weller RO (2008) Solutes, but not cells, drain from the brain parenchyma along basement membranes of capillaries and arteries: significance for cerebral amyloid angiopathy and neuroimmunology. Neuropathol Appl Neurobiol 34:131–144. https://doi.org/10.1111/j.1365-2990.2007.00926.x PubMedCrossRef

25.

Chen RL, Athauda SBP, Kassem NA, Zhang Y, Segal MB, Preston JE (2005) Decrease of transthyretin synthesis at the blood-cerebrospinal fluid barrier of old sheep. J Gerontol A Biol Sci Med Sci 60:852–858PubMedCrossRef

26.

Chen RL, Kassem NA, Sadeghi M, Preston JE (2008) Insulin-like growth factor-II uptake into choroid plexus and brain of young and old sheep. J Gerontol A Biol Sci Med Sci 63:141–148PubMedCrossRef

27.

Chen RL, Sage EA, Dunn MJ, Wait R, Preston JE (2006) Optimising ovine cerebrospinal fluid preparation for two-dimensional gel electrophoresis. Proteomics 6:3170–3175. https://doi.org/10.1002/pmic.200500623 PubMedCrossRef

28.

Chen Y (2012) Organophosphate-induced brain damage: mechanisms, neuropsychiatric and neurological consequences, and potential therapeutic strategies. Neurotoxicology 33:391–400. https://doi.org/10.1016/j.neuro.2012.03.011 PubMedCrossRef

29.

Choi D, Lee TH, Spinelli C, Chennakrishnaiah S, D’Asti E, Rak J (2017) Extracellular vesicle communication pathways as regulatory targets of oncogenic transformation. Semin Cell Dev Biol 67:11–22. https://doi.org/10.1016/j.semcdb.2017.01.003 PubMedCrossRef

30.

Cloyd MW, Low FN (1974) Scanning electron microscopy of the subarachnoid space in the dog. I. Spinal cord levels. J Comp Neurol 153:325–368. https://doi.org/10.1002/cne.901530402 PubMedCrossRef

31.

Costanzo M, Zurzolo C (2013) The cell biology of prion-like spread of protein aggregates: mechanisms and implication in neurodegeneration. Biochem J 452:1–17. https://doi.org/10.1042/BJ20121898 PubMedCrossRef

32.

Cserr HF (1974) Relationship between cerebrospinal fluid and interstitial fluid of brain. Fed Proc 33:2075–2078PubMed

33.

Cserr HF, Cooper DN, Milhorat TH (1977) Flow of cerebral interstitial fluid as indicated by the removal of extracellular markers from rat caudate nucleus. Exp Eye Res 25(Suppl):461–473. https://doi.org/10.1016/S0014-4835(77)80041-9 PubMedCrossRef

34.

Cserr HF, Cooper DN, Suri PK, Patlak CS (1981) Efflux of radiolabeled polyethylene glycols and albumin from rat brain. Am J Physiol 240:F319–F328PubMed

35.

Cserr HF, Depasquale M, Patlak CS, Pullen RG (1986) Convection of cerebral interstitial fluid and its role in brain volume regulation. Ann N Y Acad Sci 481:123–134PubMedCrossRef

36.

Cserr HF, Ostrach LH (1974) Bulk flow of interstitial fluid after intracranial injection of blue dextran 2000. Exp Neurol 45:50–60. https://doi.org/10.1016/0014-4886(74)90099-5 PubMedCrossRef

37.

Cserr HF, Patlak CS (1992) Secretion and bulk flow of interstitial fluid. In: Bradbury MW (ed) Physiology and pharmacology of the blood–brain barrier. Springer, Berlin, pp 245–261CrossRef

38.

Cushing H (1914) Studies on the cerebro-spinal fluid: I. Introduction. J Med Res 31:1–19PubMedPubMedCentral

39.

Cutler RW, Deuel RK, Barlow CF (1967) Albumin exchange between plasma and cerebrospinal fluid. Arch Neurol 17:261–270PubMedCrossRef

40.

Dandy WE (1919) Experimental hydrocephalus. Ann Surg 70:129–142PubMedPubMedCentralCrossRef

41.

Davson H (1967) Physiology of the cerebrospinal fluid. Churchill, London

42.

Davson H, Kleeman CR, Levin E (1962) Quantitative studies of the passage of different substances out of the cerebrospinal fluid. J Physiol 161:126–142PubMedPubMedCentralCrossRef

43.

Davson H, Segal MB (1970) The effects of some inhibitors and accelerators of sodium transport on the turnover of ²²Na in the cerebrospinal fluid and the brain. J Physiol 209:131–153PubMedPubMedCentralCrossRef

44.

Davson H, Segal MB (1995) Phyioslogy of the CSF and blood–brain barriers, 1st edn. CRC Press Inc, Boca Raton

45.

Davson H, Welch K, Segal MB (1987) Physiology and pathophysiology of the cerebrospinal fluid. Churchill Livingstone, Edinburgh

46.

Deisenhammer F (2015) The history of cerebrospinal fluid. In: Deisenhammer F, Sellebjerg F, Teunissen C, Tumani H (eds) Cerebrospinal fluid in clinical neurology. Springer International Publishing, Cham, pp 3–16

47.

Deng YY, Shen FC, Xie D, Han QP, Fang M, Chen CB, Zeng HK (2016) Progress in drug treatment of cerebral edema. Mini Rev Med Chem 16:917–925PubMedCrossRef

48.

Diem AK, MacGregor Sharp M, Gatherer M, Bressloff NW, Carare RO, Richardson G (2017) Arterial pulsations cannot drive intramural periarterial drainage: significance for Aβ drainage. Front Neurosci 11:475. https://doi.org/10.3389/fnins.2017.00475 PubMedPubMedCentralCrossRef

49.

Dilmen N (2005) MRI showing pulsation of CSF. https://commons.wikimedia.org/wiki/File:NPH_MRI_272_GILD.gif. Accessed 2 Oct 2017

50.

Ding F, O’donnell J, Xu Q, Kang N, Goldman N, Nedergaard M (2016) Changes in the composition of brain interstitial ions control the sleep-wake cycle. Science (80-) 352:550–555. https://doi.org/10.1126/science.aad4821 CrossRef

51.

Dolman D, Drndarski S, Abbott NJ, Rattray M (2005) Induction of aquaporin 1 but not aquaporin 4 messenger RNA in rat primary brain microvessel endothelial cells in culture. J Neurochem 93:825–833. https://doi.org/10.1111/j.1471-4159.2005.03111.x PubMedCrossRef

52.

Doran A, Obach RS, Smith BJ, Hosea NA, Becker S, Callegari E, Chen C, Chen X, Choo E, Cianfrogna J, Cox LM, Gibbs JP, Gibbs MA, Hatch H, Hop CECA, Kasman IN, Laperle J, Liu J, Liu X, Logman M, Maclin D, Nedza FM, Nelson F, Olson E, Rahematpura S, Raunig D, Rogers S, Schmidt K, Spracklin DK, Szewc M, Troutman M, Tseng E, Tu M, Van Deusen JW, Venkatakrishnan K, Walens G, Wang EQ, Wong D, Yasgar AS, Zhang C (2005) The impact of P-glycoprotein on the disposition of drugs targeted for indications of the central nervous system: evaluation using the MDR1A/1B knockout mouse model. Drug Metab Dispos 33:165–174. https://doi.org/10.1124/dmd.104.001230 PubMedCrossRef

53.

Doubal FN, MacLullich AMJ, Ferguson KJ, Dennis MS, Wardlaw JM (2010) Enlarged perivascular spaces on MRI are a feature of cerebral small vessel disease. Stroke 41:450–454. https://doi.org/10.1161/STROKEAHA.109.564914 PubMedCrossRef

54.

Dreha-Kulaczewski S, Joseph AA, Merboldt K-D, Ludwig H-C, Gärtner J, Frahm J (2015) Inspiration is the major regulator of human CSF flow. J Neurosci 35:2485–2491. https://doi.org/10.1523/JNEUROSCI.3246-14.2015 PubMedCrossRef

55.

Dreier JP, Lemale CL, Kola V, Friedman A, Schoknecht K (2017) Spreading depolarization is not an epiphenomenon but the principal mechanism of the cytotoxic edema in various gray matter structures of the brain during stroke. Neuropharmacology. https://doi.org/10.1016/j.neuropharm.2017.09.027 PubMed

56.

Dubocovich ML, Hudson RL, Sumaya IC, Masana MI, Manna E (2005) Effect of MT1 melatonin receptor deletion on melatonin-mediated phase shift of circadian rhythms in the C57BL/6 mouse. J Pineal Res 39:113–120. https://doi.org/10.1111/j.1600-079X.2005.00230.x PubMedCrossRef

57.

Engelhardt B, Carare RO, Bechmann I, Flügel A, Laman JD, Weller RO (2016) Vascular, glial, and lymphatic immune gateways of the central nervous system. Acta Neuropathol 132:317–338. https://doi.org/10.1007/s00401-016-1606-5 PubMedPubMedCentralCrossRef

58.

Engelhardt B, Vajkoczy P, Weller RO (2017) The movers and shapers in immune privilege of the CNS. Nat Immunol 18:123–131PubMedCrossRef

59.

Faber WM (1937) The nasal mucosa and the subarachnoid space. Am J Anat 62:121–148. https://doi.org/10.1002/aja.1000620106 CrossRef

60.

Fenstermacher JD, Patlak CS (1976) The movements of water and solutes in the brains of mammals. In: Pappius HM, Feindel W (eds) Dynamics of brain edema. Springer, Berlin, pp 87–94CrossRef

61.

Földi M (1996) The brain and the lymphatic system (I). Lymphology 29:1–9PubMed

62.

Förster C (2008) Tight junctions and the modulation of barrier function in disease. Histochem Cell Biol 130:55–70. https://doi.org/10.1007/s00418-008-0424-9 PubMedPubMedCentralCrossRef

63.

Frederickson RG, Low FN (1969) Blood vessels and tissue space associated with the brain of the rat. Am J Anat 125:123–145. https://doi.org/10.1002/aja.1001250202 PubMedCrossRef

64.

Gaete PS, Lillo MA, Figueroa XF (2014) Functional role of connexins and pannexins in the interaction between vascular and nervous system. J Cell Physiol 229:1336–1345. https://doi.org/10.1002/jcp.24563 PubMedCrossRef

65.

Gakuba C, Gaberel T, Goursaud S, Bourges J, di Palma C, Quenault A, de Lizarrondo SM, Vivien D, Gauberti M (2018) General anesthesia inhibits the activity of the “glymphatic system”. Theranostics 8:710–722. https://doi.org/10.7150/thno.19154 PubMedPubMedCentralCrossRef

66.

Galea I, Bechmann I, Perry VH (2007) What is immune privilege (not)? Trends Immunol 28:12–18. https://doi.org/10.1016/j.it.2006.11.004 PubMedCrossRef

67.

Gess B, Sevimli S, Strecker J-K, Young P, Schäbitz W-R (2011) Sodium-dependent vitamin C transporter 2 (SVCT2) expression and activity in brain capillary endothelial cells after transient ischemia in mice. PLoS One 6:e17139. https://doi.org/10.1371/journal.pone.0017139 PubMedPubMedCentralCrossRef

68.

Ghersi-Egea JF, Finnegan W, Chen JL, Fenstermacher JD, Hospital HF (1996) Rapid distribution of intraventricularly administered sucrose into cerebrospinal fluid cisterns via subarachnoid velae in rat. Neuroscience 75:1271–1288. https://doi.org/10.1016/0306-4522(96)00281-3 PubMedCrossRef

69.

Ghersi-Egea JF, Gorevic PD, Ghiso J, Frangione B, Patlak CS, Fenstermacher JD (1996) Fate of cerebrospinal fluid-borne amyloid beta-peptide: rapid clearance into blood and appreciable accumulation by cerebral arteries. J Neurochem 67:880–883. https://doi.org/10.1046/j.1471-4159.1996.67020880.x PubMedCrossRef

70.

Greenberg SM, Salman RAS, Biessels GJ, van Buchem M, Cordonnier C, Lee J, Montaner J, Schneider JA, Smith EE, Vernooij M, Werring DJ (2014) Outcome markers for clinical trials in cerebral amyloid angiopathy. Lancet Neurol 13:419–428. https://doi.org/10.1016/S1474-4422(14)70003-1 PubMedPubMedCentralCrossRef

71.

Griffoni C, Toni M, Spisni E, Bianco M, Santi S, Riccio M, Tomasi V (2003) The cellular prion protein: biochemistry, topology, and physiologic functions. Cell Biochem Biophys 38:287–304PubMedCrossRef

72.

Gutiérrez AM, González E, Echevarría M, Hernández CS, Whittembury G (1995) The proximal straight tubule (PST) basolateral cell membrane water channel: selectivity characteristics. J Membr Biol 143:189–197PubMedCrossRef

73.

Haj-Yasein NN, Vindedal GF, Eilert-Olsen M, Gundersen GA, Skare Ø, Laake P, Klungland A, Thorén AE, Burkhardt JM, Ottersen OP, Nagelhus EA (2011) Glial-conditional deletion of aquaporin-4 (Aqp4) reduces blood–brain water uptake and confers barrier function on perivascular astrocyte endfeet. Proc Natl Acad Sci USA 108:17815–17820. https://doi.org/10.1073/pnas.1110655108 PubMedPubMedCentralCrossRef

74.

Hannocks M-J, Pizzo ME, Huppert J, Despande T, Abbott NJ, Thorne RG, Sorokin L (2017) Molecular characterization of perivascular drainage pathways in the murine brain. J Cereb Blood Flow Metab. https://doi.org/10.1177/0271678X17749689 PubMed

75.

Van Harreveld A (1972) The extracellular space in the vertebrate central nervous system. In: Bourne G (ed) The structure and function of nervous tissue, vol 4. Academic Press, New York, pp 447–511CrossRef

76.

Härtig W, Derouiche A, Welt K, Brauer K, Grosche J, Mäder M, Reichenbach A, Brückner G (1999) Cortical neurons immunoreactive for the potassium channel Kv3.1b subunit are predominantly surrounded by perineuronal nets presumed as a buffering system for cations. Brain Res 842:15–29. https://doi.org/10.1016/S0006-8993(99)01784-9 PubMedCrossRef

77.

Hladky SB, Barrand MA (2014) Mechanisms of fluid movement into, through and out of the brain: evaluation of the evidence. Fluids Barriers CNS 11:26. https://doi.org/10.1186/2045-8118-11-26 PubMedPubMedCentralCrossRef

78.

Hladky SB, Barrand MA (2016) Fluid and ion transfer across the blood–brain and blood–cerebrospinal fluid barriers; a comparative account of mechanisms and roles. Fluids Barriers CNS 13:19. https://doi.org/10.1186/s12987-016-0040-3 PubMedPubMedCentralCrossRef

79.

Holmes BB, Diamond MI (2012) Cellular mechanisms of protein aggregate propagation. Curr Opin Neurol 25:721–726. https://doi.org/10.1097/WCO.0b013e32835a3ee0 PubMedPubMedCentralCrossRef

80.

Holter KE, Kehlet B, Devor A, Sejnowski TJ, Dale AM, Omholt SW, Ottersen OP, Nagelhus EA, Mardal K-A, Pettersen KH (2017) Interstitial solute transport in 3D reconstructed neuropil occurs by diffusion rather than bulk flow. Proc Natl Acad Sci USA 114:9894–9899. https://doi.org/10.1073/pnas.1706942114 PubMedPubMedCentralCrossRef

81.

Horstmann E, Meves H (1959) Die Feinstruktur des molekularen Rindengraues und ihre physiologische Bedeutung. Zeitschrift für Zellforsch und Mikroskopische Anat 49:569–604. https://doi.org/10.1007/BF00338866 CrossRef

82.

Hossmann KA (1976) Development and resolution of ischemic brain swelling. In: Pappius HM, Feindel W (eds) Dynamics of brain edema. Springer, Berlin, pp 219–227CrossRef

83.

Hrabetová S, Masri D, Tao L, Xiao F, Nicholson C (2009) Calcium diffusion enhanced after cleavage of negatively charged components of brain extracellular matrix by chondroitinase ABC. J Physiol 587:4029–4049. https://doi.org/10.1113/jphysiol.2009.170092 PubMedPubMedCentralCrossRef

84.

Hsu Y, Tran M, Linninger AA (2015) Dynamic regulation of aquaporin-4 water channels in neurological disorders. Croat Med J 56:401–421. https://doi.org/10.3325/cmj.2015.56.401 PubMedPubMedCentralCrossRef

85.

Huang W-J, Chen W-W, Zhang X (2015) Prions mediated neurodegenerative disorders. Eur Rev Med Pharmacol Sci 19:4028–4034PubMed

86.

Huber JD, Egleton RD, Davis TP (2001) Molecular physiology and pathophysiology of tight junctions in the blood–brain barrier. Trends Neurosci 24:719–725PubMedCrossRef

87.

Iadecola C (2013) The pathobiology of vascular dementia. Neuron 80:844–866. https://doi.org/10.1016/j.neuron.2013.10.008 PubMedCrossRef

88.

Ichimura T, Fraser PAA, Cserr HF (1991) Distribution of extracellular tracers in perivascular spaces of the rat brain. Brain Res 545:103–113. https://doi.org/10.1016/0006-8993(91)91275-6 PubMedCrossRef

89.

Iliff JJ, Lee H, Yu M, Feng T, Logan J, Nedergaard M, Benveniste H (2013) Brain-wide pathway for waste clearance captured by contrast-enhanced MRI. J Clin Invest 123:1299–1309. https://doi.org/10.1172/JCI67677 PubMedPubMedCentralCrossRef

90.

Iliff JJ, Nedergaard M (2013) Is there a cerebral lymphatic system? Stroke 44:S93–S95. https://doi.org/10.1161/STROKEAHA.112.678698 PubMedPubMedCentralCrossRef

91.

Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, Benveniste H, Vates GE, Deane R, Goldman SA, Nagelhus EA, Nedergaard M (2012) A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med 4:147ra111. https://doi.org/10.1126/scitranslmed.3003748 PubMedPubMedCentralCrossRef

92.

Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, Benveniste H, Vates GE, Deane R, Goldman SA, Nagelhus EA, Nedergaard M (2012) A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med. https://doi.org/10.1126/scitranslmed.3003748 PubMedPubMedCentral

93.

Inglese M, Bomsztyk E, Gonen O, Mannon LJ, Grossman RI, Rusinek H (2005) Dilated perivascular spaces: Hallmarks of mild traumatic brain injury. Am J Neuroradiol 26:719–724. http://www.ajnr.org/content/26/4/719 PubMed

94.

Janzen W (1961) The relationship between the perivascular and the subarachnoidal space. Psychiatr Neurol Neurochir 64:37–45PubMed

95.

Jessen NA, Munk ASF, Lundgaard I, Nedergaard M (2015) The glymphatic system: a beginner’s guide. Neurochem Res 40:1–17. https://doi.org/10.1007/s11064-015-1581-6 CrossRef

96.

Jin B-J, Smith AJ, Verkman AS (2016) Spatial model of convective solute transport in brain extracellular space does not support a “glymphatic” mechanism. J Gen Physiol 148:489–501. https://doi.org/10.1085/jgp.201611684 PubMedPubMedCentralCrossRef

97.

Jones EG (1970) On the mode of entry of blood vessels into the cerebral cortex. J Anat 106:507–520PubMedPubMedCentral

98.

Jung JS, Bhat RV, Preston GM, Guggino WB, Baraban JM, Agre P (1994) Molecular characterization of an aquaporin cDNA from brain: candidate osmoreceptor and regulator of water balance. Proc Natl Acad Sci USA 91:13052–13056. https://doi.org/10.1073/pnas.91.26.13052 PubMedPubMedCentralCrossRef

99.

Kalimo H, Fredriksson K, Nordborg C, Auer RN, Olsson Y, Johansson B (1986) The spread of brain oedema in hypertensive brain injury. Med Biol 64:133–137PubMed

100.

Kervezee L, Hartman R, van den Berg D-J, Shimizu S, Emoto-Yamamoto Y, Meijer JH, de Lange ECM (2014) Diurnal variation in P-glycoprotein-mediated transport and cerebrospinal fluid turnover in the brain. AAPS J 16:1029–1037. https://doi.org/10.1208/s12248-014-9625-4 PubMedPubMedCentralCrossRef

101.

Kida S, Pantazis A, Weller RO (1993) CSF drains directly from the subarachnoid space into nasal lymphatics in the rat. Anatomy, histology and immunological significance. Neuropathol Appl Neurobiol 19:480–488. https://doi.org/10.1111/j.1365-2990.1993.tb00476.x PubMedCrossRef

102.

Kinney JP, Spacek J, Bartol TM, Bajaj CL, Harris KM, Sejnowski TJ (2013) Extracellular sheets and tunnels modulate glutamate diffusion in hippocampal neuropil. J Comp Neurol 521:448–464. https://doi.org/10.1002/cne.23181 PubMedPubMedCentralCrossRef

103.

Koh L, Zakharov A, Johnston M (2005) Integration of the subarachnoid space and lymphatics: is it time to embrace a new concept of cerebrospinal fluid absorption? Cereb Fluid Res 2:6. https://doi.org/10.1186/1743-8454-2-6 CrossRef

104.

Konsman JP, Tridon V, Dantzer R (2000) Diffusion and action of intracerebroventricularly injected interleukin-1 in the CNS. Neuroscience 101:957–967. https://doi.org/10.1016/S0306-4522(00)00403-6 PubMedCrossRef

105.

Korogod N, Petersen CCH, Knott GW (2015) Ultrastructural analysis of adult mouse neocortex comparing aldehyde perfusion with cryo fixation. Elife 4:1–17. https://doi.org/10.7554/eLife.05793 CrossRef

106.

Krämer-Albers E-M, Hill AF (2016) Extracellular vesicles: interneural shuttles of complex messages. Curr Opin Neurobiol 39:101–107. https://doi.org/10.1016/j.conb.2016.04.016 PubMedCrossRef

107.

Krisch B, Leonhardt H, Oksche A (1983) The meningeal compartments of the median eminence and the cortex. A comparative analysis in the rat. Cell Tissue Res 228:597–640PubMedCrossRef

108.

Krisch B, Leonhardt H, Oksche A (1984) Compartments and perivascular arrangement of the meninges covering the cerebral cortex of the rat. Cell Tissue Res 238:459–474PubMedCrossRef

109.

Lai AY, Dorr A, Thomason LAM, Koletar MM, Sled JG, Stefanovic B, McLaurin J (2015) Venular degeneration leads to vascular dysfunction in a transgenic model of Alzheimer’s disease. Brain 138:1046–1058. https://doi.org/10.1093/brain/awv023 PubMedCrossRef

110.

Legros C, Chesneau D, Boutin JA, Barc C, Malpaux B (2014) Melatonin from cerebrospinal fluid but not from blood reaches sheep cerebral tissues under physiological conditions. J Neuroendocrinol 26:151–163. https://doi.org/10.1111/jne.12134 PubMedCrossRef

111.

Levin VA, Fenstermacher JD, Patlak CS (1970) Sucrose and inulin space measurements of cerebral cortex in four mammalian species. Am J Physiol 219:1528–1533PubMed

112.

Lochhead JJ, Wolak DJ, Pizzo ME, Thorne RG (2015) Rapid transport within cerebral perivascular spaces underlies widespread tracer distribution in the brain after intranasal administration. J Cereb Blood Flow Metab 35:371–381. https://doi.org/10.1038/jcbfm.2014.215 PubMedCrossRef

113.

Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, Derecki NC, Castle D, Mandell JW, Lee KS, Harris TH, Kipnis J (2015) Structural and functional features of central nervous system lymphatic vessels. Nature 523:337–341. https://doi.org/10.1038/nature14432 PubMedPubMedCentralCrossRef

114.

Mathiisen TM, Lehre KP, Danbolt NC, Ottersen OP (2010) The perivascular astroglial sheath provides a complete covering of the brain microvessels: an electron microscopic 3D reconstruction. Glia 58:1094–1103. https://doi.org/10.1002/glia.20990 PubMedCrossRef

115.

Matsubara Y, Miyazaki O, Kosuga M, Okuyama T, Nosaka S (2017) Cerebral magnetic resonance findings during enzyme replacement therapy in mucopolysaccharidosis. Pediatr Radiol 47:1–11. https://doi.org/10.1007/s00247-017-3935-5 CrossRef

116.

McConnell H (1994) Historical perspective. In: McConnell H, Bianchine JR (eds) Cerebrospinal fluid in neurology and psychiatry. Springer, Boston, pp 1–4CrossRef

117.

Mehta D, Malik AB (2006) Signaling mechanisms regulating endothelial permeability. Physiol Rev 86:279–367. https://doi.org/10.1152/physrev.00012.2005 PubMedCrossRef

118.

Merlini M, Wanner D, Nitsch RM (2016) Tau pathology-dependent remodelling of cerebral arteries precedes Alzheimer’s disease-related microvascular cerebral amyloid angiopathy. Acta Neuropathol 131:737–752. https://doi.org/10.1007/s00401-016-1560-2 PubMedPubMedCentralCrossRef

119.

Milhorat TH (1969) Choroid plexus and cerebrospinal fluid production. Science 166:1514–1516PubMedCrossRef

120.

Morris AWJ, Sharp MM, Albargothy NJ, Fernandes R, Hawkes CA, Verma A, Weller RO, Carare RO (2016) Vascular basement membranes as pathways for the passage of fluid into and out of the brain. Acta Neuropathol. https://doi.org/10.1007/s00401-016-1555-z

121.

Muldoon LL, Alvarez JI, Begley DJ, Boado RJ, del Zoppo GJ, Doolittle ND, Engelhardt B, Hallenbeck JM, Lonser RR, Ohlfest JR, Prat A, Scarpa M, Smeyne RJ, Drewes LR, Neuwelt EA (2013) Immunologic privilege in the central nervous system and the blood–brain barrier. J Cereb Blood Flow Metab 33:13–21. https://doi.org/10.1038/jcbfm.2012.153 PubMedCrossRef

122.

Murphy JB, Sturm E (1922) Homoplastic and heteroplastic tumor grafts in the brain. J Am Med Assoc 79:2159–2160. https://doi.org/10.1001/jama.1922.02640260031012 CrossRef

123.

Nag S, Manias JL, Stewart DJ (2009) Pathology and new players in the pathogenesis of brain edema. Acta Neuropathol 118:197–217. https://doi.org/10.1007/s00401-009-0541-0 PubMedCrossRef

124.

Nedergaard M (2013) Neuroscience. Garbage truck of the brain. Science 340:1529–1530. https://doi.org/10.1126/science.1240514 PubMedPubMedCentralCrossRef

125.

Nedergaard M, Goldman SA (2016) Brain drain. Sci Am 314:44–49. https://doi.org/10.2753/JES1097-203X370202 PubMedPubMedCentralCrossRef

126.

Nicholson C, Phillips JM (1981) Ion diffusion modified by tortuosity and volume fraction in the extracellular microenvironment of the rat cerebellum. J Physiol 321:225–257PubMedPubMedCentralCrossRef

127.

Nicholson C, Tao L (1993) Hindered diffusion of high molecular weight compounds in brain extracellular microenvironment measured with integrative optical imaging. Biophys J 65:2277–2290. https://doi.org/10.1016/S0006-3495(93)81324-9 PubMedPubMedCentralCrossRef

128.

Nielsen S, Nagelhus EA, Amiry-Moghaddam M, Bourque C, Agre P, Ottersen OP (1997) Specialized membrane domains for water transport in glial cells: high-resolution immunogold cytochemistry of aquaporin-4 in rat brain. J Neurosci 17:171–180PubMed

129.

Nilsson C, Ståhlberg F, Thomsen C, Henriksen O, Herning M, Owman C (1992) Circadian variation in human cerebrospinal fluid production measured by magnetic resonance imaging. Am J Physiol 262:R20–R24PubMed

130.

Nualart F (2014) Vitamin C transporters, recycling and the bystander effect in the nervous system: SVCT2 versus gluts. J Stem Cell Res Ther. https://doi.org/10.4172/2157-7633.1000209

131.

Ohata K, Marmarou A (1992) Clearance of brain edema and macromolecules through the cortical extracellular space. J Neurosurg 77:387–396. https://doi.org/10.3171/jns.1992.77.3.0387 PubMedCrossRef

132.

Ohata K, Marmarou A, Povlishock JT (1990) An immunocytochemical study of protein clearance in brain infusion edema. Acta Neuropathol 81:162–177. https://doi.org/10.1007/BF00334505 PubMedCrossRef

133.

Oldendorf WH, Davson H (1967) Brain extracellular space and the sink action of cerebrospinal fluid: measurement of rabbit brain extracellular space using sucrose labeled with carbon 14. Arch Neurol 17:196–205. https://doi.org/10.1001/archneur.1967.00470260086010 PubMedCrossRef

134.

Papadopoulos MC, Manley GT, Krishna S, Verkman AS (2004) Aquaporin-4 facilitates reabsorption of excess fluid in vasogenic brain edema. FASEB J 18:1291–1293. https://doi.org/10.1096/fj.04-1723fje PubMedCrossRef

135.

Patlak CS, Fenstermacher JD (1975) Measurements of dog blood–brain transfer constants by ventriculocisternal perfusion. Am J Physiol 229:877–884PubMed

136.

Peters A, Palay SSL, Webster HD (1991) The fine structure of the nervous system: neurons and their supporting cells, 3rd edn. Oxford University Press, New York

137.

Pizzo M, Wolak DJ, Kumar NN, Brunette E, Brunnquell CL, Hannocks M-J, Abbott NJ, Meyerand ME, Sorokin L, Stanimirovic DB, Thorne RG (2017) Intrathecal antibody distribution in the rat brain: surface diffusion, perivascular transport, and osmotic enhancement of delivery. J Physiol. https://doi.org/10.1113/JP275105 PubMed

138.

Pizzo ME, Thorne RG (2017) The extracellular and perivascular spaces of the brain. In: Badaut J, Plesnila N (eds) Brain edema: from molecular mechanisms to clinical practice, 1st edn. Elsevier (Imprint: Academic Press), London, pp 103–128

139.

Pollay M, Curl F (1967) Secretion of cerebrospinal fluid by the ventricular ependyma of the rabbit. Am J Physiol 213:1031–1038.PubMed

140.

Prell GD, Khandelwal JK, Burns RS, Green JP (1989) Diurnal fluctuation in levels of histamine metabolites in cerebrospinal fluid of rhesus monkey. Agents Actions 26:279–286PubMedCrossRef

141.

Preston SD, Steart PV, Wilkinson A, Nicoll JA, Weller RO (2003) Capillary and arterial cerebral amyloid angiopathy in Alzheimer’s disease: defining the perivascular route for the elimination of amyloid beta from the human brain. Neuropathol Appl Neurobiol 29:106–117. https://doi.org/10.1046/j.1365-2990.2003.00424.x PubMedCrossRef

142.

Proescholdt MG, Hutto B, Brady LS, Herkenham M (2000) Studies of cerebrospinal fluid flow and penetration into brain following lateral ventricle and cisterna magna injections of the tracer [14C] inulin in rat. Neuroscience 95:577–592. https://doi.org/10.1016/S0306-4522(99)00417-0 PubMedCrossRef

143.

Puvenna V, Engeler M, Banjara M, Brennan C, Schreiber P, Dadas A, Bahrami A, Solanki J, Bandyopadhyay A, Morris JK, Bernick C, Ghosh C, Rapp E, Bazarian JJ, Janigro D (2016) Is phosphorylated tau unique to chronic traumatic encephalopathy? Phosphorylated tau in epileptic brain and chronic traumatic encephalopathy. Brain Res 1630:225–240. https://doi.org/10.1016/j.brainres.2015.11.007 PubMedCrossRef

144.

Rall DP, Oppelt WW, Patlak CS (1962) Extracellular space of brain as determined by diffusion of inulin from the ventricular system. Life Sci 1:43–48. https://doi.org/10.1016/0024-3205(62)90104-2 CrossRef

145.

Rapoport SI, Schapiro MB, May C (2004) Reduced brain delivery of homovanillic acid to cerebrospinal fluid during human aging. Arch Neurol 61:1721–1724. https://doi.org/10.1001/archneur.61.11.1721 PubMedCrossRef

146.

Reina MA, De Casasola ODL, Villanueva MC, López A, Machés F, De Andrés JA (2004) Ultrastructural findings in human spinal pia mater in relation to subarachnoid anesthesia. Anesth Analg 98:1479–1485. https://doi.org/10.1213/01.ANE.0000113240.09354.E9 PubMedCrossRef

147.

Reiter RJ, Tan DX, Kim SJ, Cruz MHC (2014) Delivery of pineal melatonin to the brain and SCN: role of canaliculi, cerebrospinal fluid, tanycytes and Virchow–Robin perivascular spaces. Brain Struct Funct 219:1873–1887. https://doi.org/10.1007/s00429-014-0719-7 PubMedCrossRef

148.

Rennels ML, Gregory TF, Blaumanis OR, Fujimoto K, Grady PA (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 Res 326:47–63. https://doi.org/10.1016/0006-8993(85)91383-6 PubMedCrossRef

149.

Di Rocco C, McLone DG, Shimoji T, Raimondi AJ (1975) Continuous intraventricular cerebrospinal fluid pressure recording in hydrocephalic children during wakefulness and sleep. J Neurosurg 42:683–689. https://doi.org/10.3171/jns.1975.42.6.0683 PubMedCrossRef

150.

Rosenberg GA, Kyner WT, Estrada E (1980) Bulk flow of brain interstitial fluid under normal and hyperosmolar conditions. Am J Physiol 238:F42–F49PubMed

151.

Schielke GP, Betz AL (1992) Electrolyte transport. In: Bradbury MWB (ed) Physiology and pharmacology of the blood–brain barrier. Springer, Berlin, pp 221–243CrossRef

152.

Schwartz WJ, Reppert SM (1985) Neural regulation of the circadian vasopressin rhythm in cerebrospinal fluid: a pre-eminent role for the suprachiasmatic nuclei. J Neurosci 5:2771–2778PubMed

153.

Seckl J, Lightman S (1988) Cerebrospinal fluid neurohypophysial peptides in benign intracranial hypertension. J Neurol Neurosurg Psychiatry 51:1538–1541. https://doi.org/10.1136/jnnp.51.12.1538 PubMedPubMedCentralCrossRef

154.

Serrano-Pozo A, Frosch MP, Masliah E, Hyman BT (2011) Neuropathological alterations in Alzheimer disease. Cold Spring Harb Perspect Med 1:a006189. https://doi.org/10.1101/cshperspect.a006189 PubMedPubMedCentralCrossRef

155.

Shirai Y (1921) On the transplantation of the rat sarcoma in adult heterogeneous animals. Japan Med World 1:14–15

156.

Shively SB, Horkayne-Szakaly I, Jones RV, Kelly JP, Armstrong RC, Perl DP (2016) Characterisation of interface astroglial scarring in the human brain after blast exposure: a post-mortem case series. Lancet Neurol 15:944–953. https://doi.org/10.1016/S1474-4422(16)30057-6 PubMedCrossRef

157.

Silverberg GD, Heit G, Huhn S, Jaffe RA, Chang SD, Bronte-Stewart H, Rubenstein E, Possin K, Saul TA (2001) The cerebrospinal fluid production rate is reduced in dementia of the Alzheimer’s type. Neurology 57:1763–1766. https://doi.org/10.1212/WNL.57.10.1763 PubMedCrossRef

158.

Sixt M, Engelhardt B, Pausch F, Hallmann R, Wendler O, Sorokin LM (2001) Endothelial cell laminin isoforms, laminins 8 and 10, play decisive roles in T cell recruitment across the blood–brain barrier in experimental autoimmune encephalomyelitis. J Cell Biol 153:933–945. https://doi.org/10.1083/jcb.153.5.933 PubMedPubMedCentralCrossRef

159.

Skinner DC, Malpaux B (1999) High melatonin concentrations in third ventricular cerebrospinal fluid are not due to Galen vein blood recirculating through the choroid plexus. Endocrinology 140:4399–4405. https://doi.org/10.1210/endo.140.10.7074 PubMedCrossRef

160.

Slats D, Claassen JAHR, Spies PE, Borm G, Besse KTC, van Aalst W, Tseng J, Sjögren MJC, Olde Rikkert MGM, Verbeek MM (2012) Hourly variability of cerebrospinal fluid biomarkers in Alzheimer’s disease subjects and healthy older volunteers. Neurobiol Aging 33:831.e1–831.e9. https://doi.org/10.1016/j.neurobiolaging.2011.07.008 CrossRef

161.

Smith AJ, Jin B, Verkman AS (2015) Muddying the water in brain edema? Trends Neurosci 38:1–2. https://doi.org/10.1016/j.tins.2015.04.006 CrossRef

162.

Smith AJ, Yao X, Dix JA, Jin B, Verkman AS (2017) Test of the “glymphatic” hypothesis demonstrates diffusive and aquaporin-4-independent solute transport in rodent brain parenchyma. Elife. https://doi.org/10.7554/eLife.27679

163.

Sotiriou S, Gispert S, Cheng J, Wang Y, Chen A, Hoogstraten-Miller S, Miller GF, Kwon O, Levine M, Guttentag SH, Nussbaum RL (2002) Ascorbic-acid transporter Slc23a1 is essential for vitamin C transport into the brain and for perinatal survival. Nat Med 8:514–517. https://doi.org/10.1038/nm0502-514 PubMedCrossRef

164.

Spector R (2014) Vitamin transport diseases of brain: focus on folates, thiamine and riboflavin. Brain Disord Ther 3:120CrossRef

165.

Spector R, Johanson CE (2014) The nexus of vitamin homeostasis and DNA synthesis and modification in mammalian brain. Mol Brain 7:3. https://doi.org/10.1186/1756-6606-7-3 PubMedPubMedCentralCrossRef

166.

Spector R, Keep RF, Snodgrass SR, Smith QR, Johanson CE (2015) A balanced view of choroid plexus structure and function: focus on adult humans. Exp Neurol 267:78–86. https://doi.org/10.1016/j.expneurol.2015.02.032 PubMedCrossRef

167.

Stevenson PG, Hawke S, Sloan DJ, Bangham CR (1997) The immunogenicity of intracerebral virus infection depends on anatomical site. J Virol 71:145–151PubMedPubMedCentral

168.

Strbian D, Kovanen PT, Karjalainen-Lindsberg M-L, Tatlisumak T, Lindsberg PJ (2009) An emerging role of mast cells in cerebral ischemia and hemorrhage. Ann Med 41:438–450. https://doi.org/10.1080/07853890902887303 PubMedCrossRef

169.

Stylianopoulou F, Herbert J, Soares MB, Efstratiadis A (1988) Expression of the insulin-like growth factor II gene in the choroid plexus and the leptomeninges of the adult rat central nervous system. Proc Natl Acad Sci USA 85:141–145. https://doi.org/10.1073/pnas.85.1.141 PubMedPubMedCentralCrossRef

170.

Sweetman B, Linninger AA (2011) Cerebrospinal fluid flow dynamics in the central nervous system. Ann Biomed Eng 39:484–496. https://doi.org/10.1007/s10439-010-0141-0 PubMedCrossRef

171.

Syková E, Nicholson C (2008) Diffusion in brain extracellular space. Physiol Rev 88:1277–1340. https://doi.org/10.1152/physrev.00027.2007 PubMedPubMedCentralCrossRef

172.

Szentistványi I, Patlak CS, Ellis RA, Cserr HF (1984) Drainage of interstitial fluid from different regions of rat brain. Am J Physiol 246:35–44

173.

Taipale J, Keski-Oja J (1997) Growth factors in the extracellular matrix. FASEB J 11:51–59PubMedCrossRef

174.

Tan DX, Manchester LC, Reiter RJ (2016) CSF generation by pineal gland results in a robust melatonin circadian rhythm in the third ventricle as an unique light/dark signal. Med Hypotheses 86:3–9. https://doi.org/10.1016/j.mehy.2015.11.018 PubMedCrossRef

175.

Tasker RC, Acerini CL (2014) Cerebral edema in children with diabetic ketoacidosis: vasogenic rather than cellular? Pediatr Diabetes 15:261–270. https://doi.org/10.1111/pedi.12153 PubMedCrossRef

176.

Thal DR, Grinberg LT, Attems J (2012) Vascular dementia: different forms of vessel disorders contribute to the development of dementia in the elderly brain. Exp Gerontol 47:816–824. https://doi.org/10.1016/j.exger.2012.05.023 PubMedPubMedCentralCrossRef

177.

Thorne RG (2014) Primer on central nervous system structure/function and the vasculature, ventricular system, and fluids of the brain. In: Hammarlund-Udenaes M, de Lange E, Thorne RG (eds) Drug delivery to the brain. Physiological concepts, methodologies and approaches. Springer, New York, pp 685–707

178.

Thorne RG, Hrabetová S, Nicholson C (2004) Diffusion of epidermal growth factor in rat brain extracellular space measured by integrative optical imaging. J Neurophysiol 92:3471–3481. https://doi.org/10.1152/jn.00352.2004 PubMedCrossRef

179.

Thorne RG, Lakkaraju A, Rodriguez-Boulan E, Nicholson C (2008) In vivo diffusion of lactoferrin in brain extracellular space is regulated by interactions with heparan sulfate. Proc Natl Acad Sci USA 105:8416–8421. https://doi.org/10.1073/pnas.0711345105 PubMedPubMedCentralCrossRef

180.

Thorne RG, Nicholson C (2006) In vivo diffusion analysis with quantum dots and dextrans predicts the width of brain extracellular space. Proc Natl Acad Sci USA 103:5567–5572. https://doi.org/10.1073/pnas.0509425103 PubMedPubMedCentralCrossRef

181.

Thorne RG, Pronk GJ, Padmanabhan V, Frey WH (2004) Delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration. Neuroscience 127:481–496. https://doi.org/10.1016/j.neuroscience.2004.05.029 PubMedCrossRef

182.

Tietz S, Engelhardt B (2015) Brain barriers: crosstalk between complex tight junctions and adherens junctions. J Cell Biol 209:493–506. https://doi.org/10.1083/jcb.201412147 PubMedPubMedCentralCrossRef

183.

Tricoire H, Locatelli A, Chemineau P, Malpaux B (2002) Melatonin enters the cerebrospinal fluid through the pineal recess. Endocrinology 143:84–90. https://doi.org/10.1210/endo.143.1.8585 PubMedCrossRef

184.

Valdinocci D, Radford RAW, Siow SM, Chung RS, Pountney DL (2017) Potential modes of intercellular α-synuclein transmission. Int J Mol Sci. https://doi.org/10.3390/ijms18020469 PubMedPubMedCentral

185.

Wagner HJ, Pilgrim C, Brandl J (1974) Penetration and removal of horseradish peroxidase injected into the cerebrospinal fluid: role of cerebral perivascular spaces, endothelium and microglia. Acta Neuropathol 27:299–315. https://doi.org/10.1007/BF00690695 PubMedCrossRef

186.

Weed L (1914) Studies on cerebro-spinal fluid. No. IV: the dual source of cerebro-spinal fluid. J Med Res 31:93–118PubMedPubMedCentral

187.

Welch K (1963) Secretion of cerebrospinal fluid by choroid plexus of the rabbit. Am J Physiol 205:617–624PubMed

188.

Weller RO, Kida S, Zhang ET (1992) Pathways of fluid drainage from the brain–morphological aspects and immunological significance in rat and man. Brain Pathol 2:277–284. https://doi.org/10.1111/j.1750-3639.1992.tb00704.x PubMedCrossRef

189.

Weller RO, Subash M, Preston SD, Mazanti I, Carare RO (2008) Perivascular drainage of amyloid-beta peptides from the brain and its failure in cerebral amyloid angiopathy and Alzheimer’s disease. Brain Pathol 18:253–266. https://doi.org/10.1111/j.1750-3639.2008.00133.x PubMedCrossRef

190.

Winkler EA, Minter D, Yue JK, Manley GT (2016) Cerebral edema in traumatic brain injury: pathophysiology and prospective therapeutic targets. Neurosurg Clin N Am 27:473–488. https://doi.org/10.1016/j.nec.2016.05.008 PubMedCrossRef

191.

Wolak DJ, Pizzo ME, Thorne RG (2015) Probing the extracellular diffusion of antibodies in brain using in vivo integrative optical imaging and ex vivo fluorescence imaging. J Control Release 197:78–86. https://doi.org/10.1016/j.jconrel.2014.10.034 PubMedCrossRef

192.

Wolak DJ, Thorne RG (2013) Diffusion of macromolecules in the brain: implications for drug delivery. Mol Pharm 10:1492–1504. https://doi.org/10.1021/mp300495e PubMedPubMedCentralCrossRef

193.

Woollam DHM, Millen JW (1954) Perivascular spaces of the mammalian central nervous system. Biol Rev 29:251–283. https://doi.org/10.1111/j.1469-185X.1954.tb00597.x CrossRef

194.

Wu C, Ivars F, Anderson P, Hallmann R, Vestweber D, Nilsson P, Robenek H, Tryggvason K, Song J, Korpos E, Loser K, Beissert S, Georges-Labouesse E, Sorokin LM (2009) Endothelial basement membrane laminin alpha5 selectively inhibits T lymphocyte extravasation into the brain. Nat Med 15:519–527. https://doi.org/10.1038/nm.1957 PubMedCrossRef

195.

Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, O’Donnell J, Christensen DJ, Nicholson C, Iliff JJ, Takano T, Deane R, Nedergaard M (2013) Sleep drives metabolite clearance from the adult brain. Science 342:373–377. https://doi.org/10.1126/science.1241224 PubMedCrossRef

196.

Yao X, Hrabetova S, Nicholson C, Manley GT (2008) Aquaporin-4-deficient mice have increased extracellular space without tortuosity change. J Neurosci 28:5460–5464. https://doi.org/10.1523/JNEUROSCI.0257-08.2008 PubMedPubMedCentralCrossRef

197.

Zabel MD, Reid C (2015) A brief history of prions. Pathog Dis 73. https://doi.org/10.1093/femspd/ftv087

198.

Zafeiriou DI, Batzios SP (2013) Brain and spinal MR imaging findings in mucopolysaccharidoses: a review. Am J Neuroradiol 34:5–13. https://doi.org/10.3174/ajnr.A2832 PubMedCrossRef

199.

Zervas NT, Liszczak TM, Mayberg MR, Black PM (1982) Cerebrospinal fluid may nourish cerebral vessels through pathways in the adventitia that may be analogous to systemic vasa vasorum. J Neurosurg 56:475–481. https://doi.org/10.3171/jns.1982.56.4.0475 PubMedCrossRef

200.

Zhang ET, Inman CB, Weller RO (1990) Interrelationships of the pia mater and the perivascular (Virchow–Robin) spaces in the human cerebrum. J Anat 170:111–123PubMedPubMedCentral

201.

del Zoppo GJ, Milner R (2006) Integrin-matrix interactions in the cerebral microvasculature. Arterioscler Thromb Vasc Biol 26:1966–1975. https://doi.org/10.1161/01.ATV.0000232525.65682.a2 PubMedCrossRef

Title: The role of brain barriers in fluid movement in the CNS: is there a ‘glymphatic’ system?
Authors: N. Joan Abbott
Michelle E. Pizzo
Jane E. Preston
Damir Janigro
Robert G. Thorne
Publication date: 01-03-2018
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 3/2018
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-018-1812-4

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

The role of brain barriers in fluid movement in the CNS: is there a ‘glymphatic’ system?

Abstract

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2018

Functional morphology of the blood–brain barrier in health and disease

Neuronal complex I deficiency occurs throughout the Parkinson’s disease brain, but is not associated with neurodegeneration or mitochondrial DNA damage

A zebrafish model for C9orf72 ALS reveals RNA toxicity as a pathogenic mechanism

RNA versus protein toxicity in C9orf72 ALS/FTLD

Sense-encoded poly-GR dipeptide repeat proteins correlate to neurodegeneration and uniquely co-localize with TDP-43 in dendrites of repeat-expanded C9orf72 amyotrophic lateral sclerosis

Cluster: barriers of the central nervous system