Neurochemical Research

, Volume 40, Issue 12, pp 2583–2599 | Cite as

The Glymphatic System: A Beginner’s Guide

  • Nadia Aalling JessenEmail author
  • Anne Sofie Finmann Munk
  • Iben Lundgaard
  • Maiken Nedergaard
Original Paper


The glymphatic system is a recently discovered macroscopic waste clearance system that utilizes a unique system of perivascular tunnels, formed by astroglial cells, to promote efficient elimination of soluble proteins and metabolites from the central nervous system. Besides waste elimination, the glymphatic system also facilitates  brain-wide distribution of several compounds, including glucose, lipids, amino acids, growth factors, and neuromodulators. Intriguingly, the glymphatic system function mainly during sleep and is largely disengaged during wakefulness. The biological need for sleep across all species may therefore reflect that the brain must enter a state of activity that enables elimination of potentially neurotoxic waste products, including β-amyloid. Since the concept of the glymphatic system is relatively new, we will here review its basic structural elements, organization, regulation, and functions. We will also discuss recent studies indicating that glymphatic function is suppressed in various diseases and that failure of glymphatic function in turn might contribute to pathology in neurodegenerative disorders, traumatic brain injury and stroke.


The glymphatic system Astrocytes Perivascular spaces Virchow–Robin spaces Cerebrospinal fluid secretion Sleep Aging Neurodegenerative diseases Traumatic brain injury 



This study was supported by NIH (NINDS NS075177 and NS078304). We thank Gerry Dienel, Ben Kress, and Rashid Deane for comments on the manuscript and Takahiro Takano for illustrations.

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Liao S, Padera TP (2013) Lymphatic function and immune regulation in health and disease. Lymphat Res Biol 11:136–143. doi: 10.1089/lrb.2013.0012 PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Wang Z, Ying Z, Bosy-Westphal A et al (2012) Evaluation of specific metabolic rates of major organs and tissues: comparison between nonobese and obese women. Obesity 20:95–100. doi: 10.1038/oby.2011.256 PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Weed LH (1917) An anatomical consideration of the cerebro-spinal fluid. Anat Rec 12:461–496. doi: 10.1002/ar.1090120405 CrossRefGoogle Scholar
  4. 4.
    Johanson CE, Duncan JA, Klinge PM et al (2008) Multiplicity of cerebrospinal fluid functions: new challenges in health and disease. Cerebrospinal Fluid Res 5:10. doi: 10.1186/1743-8454-5-10 PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Damkier HH, Brown PD, Praetorius J (2013) Cerebrospinal fluid secretion by the choroid plexus. Physiol Rev 93:1847–1892. doi: 10.1152/physrev.00004.2013 PubMedCrossRefGoogle Scholar
  6. 6.
    Thrane AS, Rangroo Thrane V, Nedergaard M (2014) Drowning stars: reassessing the role of astrocytes in brain edema. Trends Neurosci 37:620–628. doi: 10.1016/j.tins.2014.08.010 PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Keep RF, Jones HC (1990) A morphometric study on the development of the lateral ventricle choroid plexus, choroid plexus capillaries and ventricular ependyma in the rat. Brain Res Dev Brain Res 56:47–53. doi: 10.1016/0165-3806(90)90163-S PubMedCrossRefGoogle Scholar
  8. 8.
    Banizs B, Pike MM, Millican CL et al (2005) Dysfunctional cilia lead to altered ependyma and choroid plexus function, and result in the formation of hydrocephalus. Development 132:5329–5339. doi: 10.1242/dev.02153 PubMedCrossRefGoogle Scholar
  9. 9.
    Brown P, Davies S, Speake T, Millar I (2004) Molecular mechanisms of cerebrospinal fluid production. Neuroscience 129:957–970. doi: 10.1016/j.neuroscience.2004.07.003 PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Ames A, Higashi K, Nesbett FB (1965) Effects of Pco2 acetazolamide and ouabain on volume and composition of choroid-plexus fluid. J Physiol 181:516–524PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Johanson CE (2008) Choroid plexus–Cerebrospinal fluid circulatory dynamics: impact on brain growth, metabolism, and repair. Neurosci, MedGoogle Scholar
  12. 12.
    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 209:131–153PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Segal MB, Burgess AM (1974) A combined physiological and morphological study of the secretory process in the rabbit choroid plexus. J Cell Sci 14:339–350PubMedGoogle Scholar
  14. 14.
    Christensen HL, Nguyen AT, Pedersen FD, Damkier HH (2013) Na(+) dependent acid-base transporters in the choroid plexus; insights from slc4 and slc9 gene deletion studies. Front Physiol 4:304. doi: 10.3389/fphys.2013.00304 PubMedCentralPubMedGoogle Scholar
  15. 15.
    Jacobs S, Ruusuvuori E, Sipilä ST et al (2008) Mice with targeted Slc4a10 gene disruption have small brain ventricles and show reduced neuronal excitability. Proc Natl Acad Sci USA 105:311–316. doi: 10.1073/pnas.0705487105 PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Damkier HH, Praetorius J (2012) Genetic ablation of Slc4a10 alters the expression pattern of transporters involved in solute movement in the mouse choroid plexus. Am J Physiol Cell Physiol 302:C1452–C1459. doi: 10.1152/ajpcell.00285.2011 PubMedCrossRefGoogle Scholar
  17. 17.
    Saito Y, Wright EM (1983) Bicarbonate transport across the frog choroid plexus and its control by cyclic nucleotides. J Physiol 336:635–648PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Mayer SE, Sanders-Bush E (1993) Sodium-dependent antiporters in choroid plexus epithelial cultures from rabbit. J Neurochem 60:1308–1316PubMedCrossRefGoogle Scholar
  19. 19.
    Deng QS, Johanson CE (1989) Stilbenes inhibit exchange of chloride between blood, choroid plexus and cerebrospinal fluid. Brain Res 501:183–187. doi: 10.1016/0006-8993(89)91041-X PubMedCrossRefGoogle Scholar
  20. 20.
    Praetorius J, Nielsen S (2006) Distribution of sodium transporters and aquaporin-1 in the human choroid plexus. Am J Physiol Cell Physiol 291:C59–C67. doi: 10.1152/ajpcell.00433.2005 PubMedCrossRefGoogle Scholar
  21. 21.
    Praetorius J (2007) Water and solute secretion by the choroid plexus. Pflugers Arch 454:1–18. doi: 10.1007/s00424-006-0170-6 PubMedCrossRefGoogle Scholar
  22. 22.
    Nielsen S, Smith BL, Christensen EI, Agre P (1993) Distribution of the aquaporin CHIP in secretory and resorptive epithelia and capillary endothelia. Proc Natl Acad Sci USA 90:7275–7279. doi: 10.1073/pnas.90.15.7275 PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Damkier HH, Brown PD, Praetorius J (2010) Epithelial pathways in choroid plexus electrolyte transport. Physiology (Bethesda) 25:239–249. doi: 10.1152/physiol.00011.2010 CrossRefGoogle Scholar
  24. 24.
    Papadopoulos MC, Verkman AS (2013) Aquaporin water channels in the nervous system. Nat Rev Neurosci 14:265–277. doi: 10.1038/nrn3468 PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Oshio K, Song Y, Verkman AS, Manley GT (2003) Aquaporin-1 deletion reduces osmotic water permeability and cerebrospinal fluid production. Acta Neurochir 86(Suppl):525–528Google Scholar
  26. 26.
    Oshio K, Watanabe H, Song Y et al (2005) Reduced cerebrospinal fluid production and intracranial pressure in mice lacking choroid plexus water channel Aquaporin-1. FASEB J 19:76–78. doi: 10.1096/fj.04-1711fje PubMedGoogle Scholar
  27. 27.
    Husted RF, Reed DJ (1976) Regulation of cerebrospinal fluid potassium by the cat choroid plexus. J Physiol 259:213–221PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Silverberg GD, Huhn S, Jaffe RA et al (2002) Downregulation of cerebrospinal fluid production in patients with chronic hydrocephalus. J Neurosurg 97:1271–1275. doi: 10.3171/jns.2002.97.6.1271 PubMedCrossRefGoogle Scholar
  29. 29.
    Lindvall M, Owman C (1981) Autonomic nerves in the mammalian choroid plexus and their influence on the formation of cerebrospinal fluid. J Cereb Blood Flow Metab 1:245–266. doi: 10.1038/jcbfm.1981.30 PubMedCrossRefGoogle Scholar
  30. 30.
    Szentistványi I, Patlak CS, Ellis RA, Cserr HF (1984) Drainage of interstitial fluid from different regions of rat brain. Am J Physiol 246:F835–F844PubMedGoogle Scholar
  31. 31.
    Johnston M, Zakharov A, Papaiconomou C et al (2004) Evidence of connections between cerebrospinal fluid and nasal lymphatic vessels in humans, non-human primates and other mammalian species. Cerebrospinal Fluid Res 1:2. doi: 10.1186/1743-8454-1-2 PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    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? Cerebrospinal Fluid Res 2:6. doi: 10.1186/1743-8454-2-6 PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Biceroglu H, Albayram S, Ogullar S et al (2012) Direct venous spinal reabsorption of cerebrospinal fluid: a new concept with serial magnetic resonance cisternography in rabbits. J Neurosurg Spine 16:394–401. doi: 10.3171/2011.12.SPINE11108 PubMedCrossRefGoogle Scholar
  34. 34.
    Murtha LA, Yang Q, Parsons MW et al (2014) Cerebrospinal fluid is drained primarily via the spinal canal and olfactory route in young and aged spontaneously hypertensive rats. Fluids Barriers CNS 11:12. doi: 10.1186/2045-8118-11-12 PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Kimelberg HK (2004) Water homeostasis in the brain: basic concepts. Neuroscience 129:851–860. doi: 10.1016/j.neuroscience.2004.07.033 PubMedCrossRefGoogle Scholar
  36. 36.
    Redzic Z (2011) Molecular biology of the blood-brain and the blood-cerebrospinal fluid barriers: similarities and differences. Fluids Barriers CNS 8:3. doi: 10.1186/2045-8118-8-3 PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Oresković D, Klarica M (2010) The formation of cerebrospinal fluid: nearly a hundred years of interpretations and misinterpretations. Brain Res Rev 64:241–262. doi: 10.1016/j.brainresrev.2010.04.006 PubMedCrossRefGoogle Scholar
  38. 38.
    Sathyanesan M, Girgenti MJ, Banasr M et al (2012) A molecular characterization of the choroid plexus and stress-induced gene regulation. Transl Psychiatry 2:e139. doi: 10.1038/tp.2012.64 PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Bulat M, Lupret V, Orehković D, Klarica M (2008) Transventricular and transpial absorption of cerebrospinal fluid into cerebral microvessels. Coll Antropol 32(Suppl 1):43–50PubMedGoogle Scholar
  40. 40.
    Orešković D, Klarica M (2014) A new look at cerebrospinal fluid movement. Fluids Barriers CNS 11:16. doi: 10.1186/2045-8118-11-16 PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Buishas J, Gould IG, Linninger AA (2014) A computational model of cerebrospinal fluid production and reabsorption driven by starling forces. Croat Med J 55:481–497. doi: 10.3325/cmj.2014.55.481 PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Kulik T, Kusano Y, Aronhime S (2008) Regulation of cerebral vasculature in normal and ischemic brain. Neuropharmacology 55:281–288. doi: 10.1016/j.neuropharm.2008.04.017 PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Prince E, Ahn S (2013) Basic vascular neuroanatomy of the brain and spine: what the general interventional radiologist needs to know. Semin Intervent Radiol 30:234–239. doi: 10.1055/s-0033-1353475 PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Zlokovic BV (2011) Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nat Rev Neurosci 12:723–738. doi: 10.1038/nrn3114 PubMedCentralPubMedGoogle Scholar
  45. 45.
    Zhang ET, Inman CB, Weller RO (1990) Interrelationships of the pia mater and the perivascular (Virchow–Robin) spaces in the human cerebrum. J Anat 170:111–123PubMedCentralPubMedGoogle Scholar
  46. 46.
    del Zoppo GJ, Moskowitz M, Nedergaard M (2015) The neurovascular unit and responses to ischemia. In: Grotta J, Albers G, Broderick J, Kasner S, Lo E, Medelow AD, Sacco R, Wong L (eds) Stroke: pathophysiology, diagnosis, and management, 6th Edn. Elsevier, Philadelphia.Google Scholar
  47. 47.
    Engelhardt B, Ransohoff RM (2012) Capture, crawl, cross: the T cell code to breach the blood–brain barriers. Trends Immunol 33:579–589. doi: 10.1016/ PubMedCrossRefGoogle Scholar
  48. 48.
    Schlesinger B (1939) The venous drainage of the brain, with special reference to the galenic system. Brain 62:274–291. doi: 10.1093/brain/62.3.274 CrossRefGoogle Scholar
  49. 49.
    Cipolla M (2010) Anatomy and ultrastructure. Cereb, CircGoogle Scholar
  50. 50.
    Iliff JJ, Wang M, Liao Y et al (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. doi:  10.1126/scitranslmed.3003748
  51. 51.
    Iliff JJ, Nedergaard M (2013) Is there a cerebral lymphatic system? Stroke 44:S93–S95. doi: 10.1161/STROKEAHA.112.678698 PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Bradbury M, Cserr H (1985) Drainage of cerebral interstitial fluid and of cerebrospinal fluid into lymphatics. In: Johnston M (ed) Experimental Biology of the lymphatic circulation. Elsevier, New York, pp 355–394Google Scholar
  53. 53.
    Weller RO, Subash M, Preston SD et al (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. doi: 10.1111/j.1750-3639.2008.00133.x PubMedCrossRefGoogle Scholar
  54. 54.
    Carare RO, Bernardes-Silva M, Newman TA et al (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. doi: 10.1111/j.1365-2990.2007.00926.x PubMedCrossRefGoogle Scholar
  55. 55.
    Hawkes CA, Härtig W, Kacza J et al (2011) Perivascular drainage of solutes is impaired in the ageing mouse brain and in the presence of cerebral amyloid angiopathy. Acta Neuropathol 121:431–443. doi: 10.1007/s00401-011-0801-7 PubMedCrossRefGoogle Scholar
  56. 56.
    Bjorkhem I, Meaney S (2004) Brain cholesterol: long secret life behind a barrier. Arter Thromb Vasc Biol 24:806–815. doi: 10.1161/01.ATV.0000120374.59826.1b CrossRefGoogle Scholar
  57. 57.
    Björkhem I, Lütjohann D, Diczfalusy U et al (1998) Cholesterol homeostasis in human brain: turnover of 24S-hydroxycholesterol and evidence for a cerebral origin of most of this oxysterol in the circulation. J Lipid Res 39:1594–1600PubMedGoogle Scholar
  58. 58.
    Lütjohann D, Breuer O, Ahlborg G et al (1996) Cholesterol homeostasis in human brain: evidence for an age-dependent flux of 24S-hydroxycholesterol from the brain into the circulation. Proc Natl Acad Sci USA 93:9799–9804. doi: 10.1073/pnas.93.18.9799 PubMedCentralPubMedCrossRefGoogle Scholar
  59. 59.
    Fagan AM, Holtzman DM, Munson G et al (1999) Unique lipoproteins secreted by primary astrocytes from wild type, apoE (−/−), and human apoE transgenic mice. J Biol Chem 274:30001–30007. doi: 10.1074/jbc.274.42.30001 PubMedCrossRefGoogle Scholar
  60. 60.
    Deane R, Sagare A, Hamm K et al (2008) apoE isoform—specific disruption of amyloid β peptide clearance from mouse brain. J Clin Invest 118:4002–4013. doi: 10.1172/JCI36663DS1 PubMedCentralPubMedCrossRefGoogle Scholar
  61. 61.
    Strittmatter WJ, Saunders AM, Schmechel D et al (1993) Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci USA 90:1977–1981. doi: 10.1073/pnas.90.5.1977 PubMedCentralPubMedCrossRefGoogle Scholar
  62. 62.
    Corder EH, Saunders AM, Strittmatter WJ et al (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261:921–923. doi: 10.1126/science.8346443 PubMedCrossRefGoogle Scholar
  63. 63.
    Boyles JK, Pitas RE, Wilson E et al (1985) Apolipoprotein E associated with astrocytic glia of the central nervous system and with nonmyelinating glia of the peripheral nervous system. J Clin Invest 76:1501–1513. doi: 10.1172/JCI112130 PubMedCentralPubMedCrossRefGoogle Scholar
  64. 64.
    Xu Q, Bernardo A, Walker D et al (2006) Profile and regulation of apolipoprotein E (ApoE) expression in the CNS in mice with targeting of green fluorescent protein gene to the ApoE locus. J Neurosci 26:4985–4994. doi: 10.1523/JNEUROSCI.5476-05.2006 PubMedCrossRefGoogle Scholar
  65. 65.
    Rangroo Thrane V, Thrane AS, Plog BA et al (2013) Paravascular microcirculation facilitates rapid lipid transport and astrocyte signaling in the brain. Sci Rep 3:2582. doi: 10.1038/srep02582 PubMedGoogle Scholar
  66. 66.
    Klose U, Strik C, Kiefer C, Grodd W (2000) Detection of a relation between respiration and CSF pulsation with an echoplanar technique. J Magn Reson Imaging 11:438–444. doi: 10.1002/(SICI)1522-2586(200004)11:4<438:AID-JMRI12>3.0.CO;2-O PubMedCrossRefGoogle Scholar
  67. 67.
    Yamada S, Miyazaki M, Yamashita Y et al (2013) Influence of respiration on cerebrospinal fluid movement using magnetic resonance spin labeling. Fluids Barriers CNS 10:36. doi: 10.1186/2045-8118-10-36 PubMedCentralPubMedCrossRefGoogle Scholar
  68. 68.
    Murfee WL, Skalak TC, Peirce SM (2005) Differential arterial/venous expression of NG2 proteoglycan in perivascular cells along microvessels: identifying a venule-specific phenotype. Microcirculation 12:151–160. doi: 10.1080/10739680590904955 PubMedCrossRefGoogle Scholar
  69. 69.
    Zhu X, Bergles DE, Nishiyama A (2008) NG2 cells generate both oligodendrocytes and gray matter astrocytes. Development 135:145–157. doi: 10.1242/dev.004895 PubMedCrossRefGoogle Scholar
  70. 70.
    Iliff JJ, Lee H, Yu M et al (2013) Brain-wide pathway for waste clearance captured by contrast-enhanced MRI. J Clin Invest 123:1299–1309. doi: 10.1172/JCI67677 PubMedCentralPubMedCrossRefGoogle Scholar
  71. 71.
    Iliff JJ, Wang M, Zeppenfeld DM et al (2013) Cerebral arterial pulsation drives paravascular CSF-interstitial fluid exchange in the murine brain. J Neurosci 33:18190–18199. doi: 10.1523/JNEUROSCI.1592-13.2013 PubMedCentralPubMedCrossRefGoogle Scholar
  72. 72.
    Schroth G, Klose U (1992) Cerebrospinal fluid flow—I. Physiology of cardiac-related pulsation. Neuroradiology 35:1–9. doi: 10.1007/BF00588270 PubMedCrossRefGoogle Scholar
  73. 73.
    Stoodley MA, Brown SA, Brown CJ, Jones NR (1997) Arterial pulsation-dependent perivascular cerebrospinal fluid flow into the central canal in the sheep spinal cord. J Neurosurg 86:686–693. doi: 10.3171/jns.1997.86.4.0686 PubMedCrossRefGoogle Scholar
  74. 74.
    Bilston LE, Stoodley MA, Fletcher DF (2010) The influence of the relative timing of arterial and subarachnoid space pulse waves on spinal perivascular cerebrospinal fluid flow as a possible factor in syrinx development. J Neurosurg 112:808–813. doi: 10.3171/2009.5.JNS08945 PubMedCrossRefGoogle Scholar
  75. 75.
    Buzsáki G (1998) Memory consolidation during sleep: a neurophysiological perspective. J Sleep Res 7(Suppl 1):17–23. doi: 10.1046/j.1365-2869.7.s1.3.x PubMedCrossRefGoogle Scholar
  76. 76.
    Fishbein W, Gutwein BM (1977) Paradoxical sleep and memory storage processes. Behav Biol 19:425–464. doi: 10.1016/S0091-6773(77)91903-4 PubMedCrossRefGoogle Scholar
  77. 77.
    Huber R, Ghilardi MF, Massimini M, Tononi G (2004) Local sleep and learning. Nature 430:78–81. doi: 10.1038/nature02663 PubMedCrossRefGoogle Scholar
  78. 78.
    Tucker MA, Hirota Y, Wamsley EJ et al (2006) A daytime nap containing solely non-REM sleep enhances declarative but not procedural memory. Neurobiol Learn Mem 86:241–247. doi: 10.1016/j.nlm.2006.03.005 PubMedCrossRefGoogle Scholar
  79. 79.
    Siegel JM (2005) Clues to the functions of mammalian sleep. Nature 437:1264–1271. doi: 10.1038/nature04285 PubMedCrossRefGoogle Scholar
  80. 80.
    Madsen PL, Schmidt JF, Wildschiødtz G et al (1991) Cerebral O2 metabolism and cerebral blood flow in humans during deep and rapid-eye-movement sleep. J Appl Physiol 70:2597–2601PubMedGoogle Scholar
  81. 81.
    Xie L, Kang H, Xu Q et al (2013) Sleep drives metabolite clearance from the adult brain. Science 342:373–377. doi: 10.1126/science.1241224 PubMedCrossRefGoogle Scholar
  82. 82.
    Berridge CW, Waterhouse BD (2003) The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes. Brain Res Rev 42:33–84. doi: 10.1016/S0165-0173(03)00143-7 PubMedCrossRefGoogle Scholar
  83. 83.
    O’Donnell J, Zeppenfeld D, McConnell E et al (2012) Norepinephrine: a neuromodulator that boosts the function of multiple cell types to optimize CNS performance. Neurochem Res 37:2496–2512. doi: 10.1007/s11064-012-0818-x PubMedCentralPubMedCrossRefGoogle Scholar
  84. 84.
    Nilsson C, Lindvall-Axelsson M, Owman C (1992) Neuroendocrine regulatory mechanisms in the choroid plexus-cerebrospinal fluid system. Brain Res Rev 17:109–138. doi: 10.1016/0165-0173(92)90011-A PubMedCrossRefGoogle Scholar
  85. 85.
    Kress BT, Iliff JJ, Xia M et al (2014) Impairment of paravascular clearance pathways in the aging brain. Ann Neurol. doi: 10.1002/ana.24271 PubMedCentralPubMedGoogle Scholar
  86. 86.
    Sabbatini M, Barili P, Bronzetti E et al (1999) Age-related changes of glial fibrillary acidic protein immunoreactive astrocytes in the rat cerebellar cortex. Mech Ageing Dev 108:165–172PubMedCrossRefGoogle Scholar
  87. 87.
    Deane R, Zlokovic BV (2007) Role of the blood-brain barrier in the pathogenesis of Alzheimer’s disease. Curr Alzheimer Res 4:191–197. doi: 10.2174/156720507780362245 PubMedCrossRefGoogle Scholar
  88. 88.
    Chen RL, Kassem NA, Redzic ZB et al (2009) Age-related changes in choroid plexus and blood-cerebrospinal fluid barrier function in the sheep. Exp Gerontol 44:289–296. doi: 10.1016/j.exger.2008.12.004 PubMedCrossRefGoogle Scholar
  89. 89.
    Fleischman D, Berdahl JP, Zaydlarova J et al (2012) Cerebrospinal fluid pressure decreases with older age. PLoS ONE 7:e52664. doi: 10.1371/journal.pone.0052664 PubMedCentralPubMedCrossRefGoogle Scholar
  90. 90.
    Zieman SJ, Melenovsky V, Kass DA (2005) Mechanisms, pathophysiology, and therapy of arterial stiffness. Arter Thromb Vasc Biol 25:932–943. doi: 10.1161/01.ATV.0000160548.78317.29 CrossRefGoogle Scholar
  91. 91.
    Ross CA, Poirier MA (2004) Protein aggregation and neurodegenerative disease. Nat Med 10(Suppl):S10–S17. doi: 10.1038/nm1066 PubMedCrossRefGoogle Scholar
  92. 92.
    Takalo M, Salminen A, Soininen H et al (2013) Protein aggregation and degradation mechanisms in neurodegenerative diseases. Am J Neurodegener Dis 2:1–14PubMedCentralPubMedGoogle Scholar
  93. 93.
    Frost B, Jacks RL, Diamond MI (2009) Propagation of tau misfolding from the outside to the inside of a cell. J Biol Chem 284:12845–12852. doi: 10.1074/jbc.M808759200 PubMedCentralPubMedCrossRefGoogle Scholar
  94. 94.
    Grad LI, Yerbury JJ, Turner BJ et al (2014) Intercellular propagated misfolding of wild-type Cu/Zn superoxide dismutase occurs via exosome-dependent and -independent mechanisms. Proc Natl Acad Sci USA 111:3620–3625. doi: 10.1073/pnas.1312245111 PubMedCentralPubMedCrossRefGoogle Scholar
  95. 95.
    Kordower JH, Chu Y, Hauser RA et al (2008) Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson’s disease. Nat Med 14:504–506. doi: 10.1038/nm1747 PubMedCrossRefGoogle Scholar
  96. 96.
    Li JY, Englund E, Holton JL et al (2008) Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation. Nat Med 14:501–503. doi: 10.1038/nm1746 PubMedCrossRefGoogle Scholar
  97. 97.
    Yamada K, Cirrito JR, Stewart FR et al (2011) In vivo microdialysis reveals age-dependent decrease of brain interstitial fluid tau levels in P301S human tau transgenic mice. J Neurosci 31:13110–13117. doi: 10.1523/JNEUROSCI.2569-11.2011 PubMedCentralPubMedCrossRefGoogle Scholar
  98. 98.
    Palop JJ, Mucke L (2010) Amyloid-beta-induced neuronal dysfunction in Alzheimer’s disease: from synapses toward neural networks. Nat Neurosci 13:812–818. doi: 10.1038/nn.2583 PubMedCentralPubMedCrossRefGoogle Scholar
  99. 99.
    Bero AW, Yan P, Roh JH et al (2011) Neuronal activity regulates the regional vulnerability to amyloid-beta deposition. Nat Neurosci 14:750–756. doi: 10.1038/nn.2801 PubMedCentralPubMedCrossRefGoogle Scholar
  100. 100.
    Skaper SD, Evans NA, Rosin C et al (2009) Oligodendrocytes are a novel source of amyloid peptide generation. Neurochem Res 34:2243–2250. doi: 10.1007/s11064-009-0022-9 PubMedCrossRefGoogle Scholar
  101. 101.
    Guo JL, Lee VM (2011) Seeding of normal Tau by pathological Tau conformers drives pathogenesis of Alzheimer-like tangles. J Biol Chem 286:15317–15331. doi: 10.1074/jbc.M110.209296 PubMedCentralPubMedCrossRefGoogle Scholar
  102. 102.
    Jucker M, Walker LC (2011) Pathogenic protein seeding in Alzheimer disease and other neurodegenerative disorders. Ann Neurol 70:532–540. doi: 10.1002/ana.22615 PubMedCentralPubMedCrossRefGoogle Scholar
  103. 103.
    Bateman RJ, Munsell LY, Morris JC et al (2006) Human amyloid-beta synthesis and clearance rates as measured in cerebrospinal fluid in vivo. Nat Med 12:856–861. doi: 10.1038/nm1438 PubMedCentralPubMedCrossRefGoogle Scholar
  104. 104.
    Sagare AP, Bell RD, Zlokovic BV (2012) Neurovascular dysfunction and faulty amyloid beta-peptide clearance in Alzheimer disease. Cold Spring Harb Perspect Med. doi: 10.1101/cshperspect.a011452 PubMedCentralPubMedGoogle Scholar
  105. 105.
    Maurizi CP (1991) Recirculation of cerebrospinal fluid through the tela choroidae is why high levels of melatonin can be found in the lateral ventricles. Med Hypotheses 35:154–158. doi: 10.1016/0306-9877(91)90041-V PubMedCrossRefGoogle Scholar
  106. 106.
    Michaud JP, Bellavance MA, Prefontaine P, Rivest S (2013) Real-time in vivo imaging reveals the ability of monocytes to clear vascular amyloid beta. Cell Rep 5:646–653. doi: 10.1016/j.celrep.2013.10.010 PubMedCrossRefGoogle Scholar
  107. 107.
    Ferrer I (2010) Cognitive impairment of vascular origin: neuropathology of cognitive impairment of vascular origin. J Neurol Sci 299:139–149. doi: 10.1016/j.jns.2010.08.039 PubMedCrossRefGoogle Scholar
  108. 108.
    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. doi: 10.1016/j.exger.2012.05.023 PubMedCentralPubMedCrossRefGoogle Scholar
  109. 109.
    Gouw AA, Seewann A, van der Flier WM et al (2011) Heterogeneity of small vessel disease: a systematic review of MRI and histopathology correlations. J Neurol Neurosurg Psychiatry 82:126–135. doi: 10.1136/jnnp.2009.204685 PubMedCrossRefGoogle Scholar
  110. 110.
    Groeschel S, Chong WK, Surtees R, Hanefeld F (2006) Virchow–Robin spaces on magnetic resonance images: normative data, their dilatation, and a review of the literature. Neuroradiology 48:745–754. doi: 10.1007/s00234-006-0112-1 PubMedCrossRefGoogle Scholar
  111. 111.
    Tournier-Lasserve E, Joutel A, Melki J et al (1993) Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps to chromosome 19q12. Nat Genet 3:256–259. doi: 10.1038/ng0393-256 PubMedCrossRefGoogle Scholar
  112. 112.
    Buerge C, Steiger G, Kneifel S et al (2011) Lobar dementia due to extreme widening of Virchow–Robin spaces in one hemisphere. Case Rep Neurol 3:136–140. doi: 10.1159/000329267 PubMedCentralPubMedCrossRefGoogle Scholar
  113. 113.
    Roher AE, Kuo Y-M, Esh C et al (2003) Cortical and leptomeningeal cerebrovascular amyloid and white matter pathology in Alzheimer’s disease. Mol Med 9:112–122PubMedCentralPubMedGoogle Scholar
  114. 114.
    Joutel A, Corpechot C, Ducros A et al (1996) Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 383:707–710. doi: 10.1038/383707a0 PubMedCrossRefGoogle Scholar
  115. 115.
    Moretti L, Cristofori I, Weaver SM et al (2012) Cognitive decline in older adults with a history of traumatic brain injury. Lancet Neurol 11:1103–1112. doi: 10.1016/S1474-4422(12)70226-0 PubMedCrossRefGoogle Scholar
  116. 116.
    Plassman BL, Havlik RJ, Steffens DC et al (2000) Documented head injury in early adulthood and risk of Alzheimer’s disease and other dementias. Neurology 55:1158–1166. doi: 10.1212/WNL.55.8.1158 PubMedCrossRefGoogle Scholar
  117. 117.
    Irimia A, Wang B, Aylward SR et al (2012) Neuroimaging of structural pathology and connectomics in traumatic brain injury: toward personalized outcome prediction. Neuroimage Clin 1:1–17. doi: 10.1016/j.nicl.2012.08.002 PubMedCentralPubMedCrossRefGoogle Scholar
  118. 118.
    Pop V, Sorensen DW, Kamper JE et al (2013) Early brain injury alters the blood-brain barrier phenotype in parallel with beta-amyloid and cognitive changes in adulthood. J Cereb Blood Flow Metab 33:205–214. doi: 10.1038/jcbfm.2012.154 PubMedCentralPubMedCrossRefGoogle Scholar
  119. 119.
    Shaw GJ, Jauch EC, Zemlan FP (2002) Serum cleaved Tau protein levels and clinical outcome in adult patients with closed head injury. Ann Emerg Med 39:254–257. doi: 10.1067/mem.2002.121214 PubMedCrossRefGoogle Scholar
  120. 120.
    Zemlan FP, Jauch EC, Mulchahey JJ et al (2002) C-tau biomarker of neuronal damage in severe brain injured patients: association with elevated intracranial pressure and clinical outcome. Brain Res 947:131–139. doi: 10.1016/S0006-8993(02)02920-7 PubMedCrossRefGoogle Scholar
  121. 121.
    Gabbita SP, Scheff SW, Menard RM et al (2005) Cleaved-tau: a biomarker of neuronal damage after traumatic brain injury. J Neurotrauma 22:83–94. doi: 10.1089/neu.2005.22.83 PubMedCrossRefGoogle Scholar
  122. 122.
    Iliff JJ, Chen MJ, Plog BA et al (2014) Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury. J Neurosci 34:16180–16193. doi: 10.1523/JNEUROSCI.3020-14.2014 PubMedCentralPubMedCrossRefGoogle Scholar
  123. 123.
    Gaberel T, Gakuba C, Goulay R et al (2014) Impaired glymphatic perfusion after strokes revealed by contrast-enhanced MRI: a new target for fibrinolysis? Stroke 45:3092–3096. doi: 10.1161/STROKEAHA.114.006617 PubMedCrossRefGoogle Scholar
  124. 124.
    Bradbury MW, Cserr HF, Westrop RJ (1981) Drainage of cerebral interstitial fluid into deep cervical lymph of the rabbit. Am J Physiol 240:F329–F336PubMedGoogle Scholar
  125. 125.
    Mondello S, Muller U, Jeromin A et al (2011) Blood-based diagnostics of traumatic brain injuries. Expert Rev Mol Diagn 11:65–78. doi: 10.1586/erm.10.104 PubMedCentralPubMedCrossRefGoogle Scholar
  126. 126.
    Plog BA, Dashnaw ML, Hitomi E et al (2015) Biomarkers of traumatic injury are transported from brain to blood via the glymphatic system. J Neurosci 35:518–526. doi: 10.1523/JNEUROSCI.3742-14.2015 PubMedCentralPubMedCrossRefGoogle Scholar
  127. 127.
    Rennels ML, Gregory TF, Blaumanis OR et al (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. doi: 10.1016/0006-8993(85)91383-6 PubMedCrossRefGoogle Scholar
  128. 128.
    Rennels ML, Blaumanis OR, Grady PA (1990) Rapid solute transport throughout the brain via paravascular fluid pathways. Adv Neurol 52:431–439PubMedGoogle Scholar
  129. 129.
    Ichimura T, Fraser PA, Cserr HF (1991) Distribution of extracellular tracers in perivascular spaces of the rat brain. Brain Res 545:103–113. doi: 10.1016/0006-8993(91)91275-6 PubMedCrossRefGoogle Scholar
  130. 130.
    Ball KK, Cruz NF, Mrak RE, Dienel GA (2010) Trafficking of glucose, lactate, and amyloid-beta from the inferior colliculus through perivascular routes. J Cereb Blood Flow Metab 30:162–176. doi: 10.1038/jcbfm.2009.206 PubMedCentralPubMedCrossRefGoogle Scholar
  131. 131.
    Gandhi GK, Cruz NF, Ball KK, Dienel GA (2009) Astrocytes are poised for lactate trafficking and release from activated brain and for supply of glucose to neurons. J Neurochem 111:522–536. doi: 10.1111/j.1471-4159.2009.06333.x PubMedCentralPubMedCrossRefGoogle Scholar
  132. 132.
    Ju Y-ES, McLeland JS, Toedebusch CD et al (2013) Sleep quality and preclinical Alzheimer disease. JAMA Neurol 70:587–593. doi: 10.1001/jamaneurol.2013.2334 PubMedCentralPubMedCrossRefGoogle Scholar
  133. 133.
    Tonsfeldt KJ, Chappell PE (2012) Clocks on top: the role of the circadian clock in the hypothalamic and pituitary regulation of endocrine physiology. Mol Cell Endocrinol 349:3–12. doi: 10.1016/j.mce.2011.07.003 PubMedCentralPubMedCrossRefGoogle Scholar
  134. 134.
    Axelrod J (1974) The pineal gland: a neurochemical transducer. Science 184:1341–1348. doi: 10.1126/science.184.4144.1341 PubMedCrossRefGoogle Scholar
  135. 135.
    Yang L, Kress BT, Weber HJ et al (2013) Evaluating glymphatic pathway function utilizing clinically relevant intrathecal infusion of CSF tracer. J Transl Med 11:107. doi: 10.1186/1479-5876-11-107 PubMedCentralPubMedCrossRefGoogle Scholar
  136. 136.
    Aydin K, Terzibasioglu E, Sencer S et al (2008) Localization of cerebrospinal fluid leaks by gadolinium-enhanced magnetic resonance cisternography: a 5-year single-center experience. Neurosurgery 62:584–589. doi: 10.1227/01.neu.0000317306.39203.24 PubMedCrossRefGoogle Scholar
  137. 137.
    Schick U, Musahl C, Papke K (2010) Diagnostics and treatment of spontaneous intracranial hypotension. Minim Invasive Neurosurg 53:15–20. doi: 10.1055/s-0030-1247552 PubMedCrossRefGoogle Scholar
  138. 138.
    Lundgaard I, Li B, Xie L et al (2015) Direct neuronal glucose uptake heralds activity-dependent increases in cerebral metabolism. Nat Commun. doi: 10.1038/ncomms7807 Google Scholar
  139. 139.
    Hadaczek P, Yamashita Y, Mirek H et al (2006) The “perivascular pump” driven by arterial pulsation is a powerful mechanism for the distribution of therapeutic molecules within the brain. Mol Ther 14:69–78. doi: 10.1016/j.ymthe.2006.02.018 PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.School of Medicine and DentistryUniversity of Rochester Medical CenterRochesterUSA

Personalised recommendations