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Perivascular spaces in the brain: anatomy, physiology and pathology

Abstract

Perivascular spaces include a variety of passageways around arterioles, capillaries and venules in the brain, along which a range of substances can move. Although perivascular spaces were first identified over 150 years ago, they have come to prominence recently owing to advances in knowledge of their roles in clearance of interstitial fluid and waste from the brain, particularly during sleep, and in the pathogenesis of small vessel disease, Alzheimer disease and other neurodegenerative and inflammatory disorders. Experimental advances have facilitated in vivo studies of perivascular space function in intact rodent models during wakefulness and sleep, and MRI in humans has enabled perivascular space morphology to be related to cognitive function, vascular risk factors, vascular and neurodegenerative brain lesions, sleep patterns and cerebral haemodynamics. Many questions about perivascular spaces remain, but what is now clear is that normal perivascular space function is important for maintaining brain health. Here, we review perivascular space anatomy, physiology and pathology, particularly as seen with MRI in humans, and consider translation from models to humans to highlight knowns, unknowns, controversies and clinical relevance.

Key points

  • Visible perivascular spaces on MRI increase in number with age, vascular risk factors (particularly hypertension) and other features of small vessel disease, indicating that they are clinically relevant.

  • Perivascular space dilation on MRI is a marker of perivascular space dysfunction and, by implication from preclinical studies, impairment of normal brain fluid and waste clearance and microvascular dysfunction.

  • Perivascular spaces can be quantified using visual scores of perivascular spaces in standard brain regions and now also with computational measures of perivascular space count, volume, length, width, sphericity and orientation.

  • Experimental models show that perivascular spaces are important conduits for uptake of cerebrospinal fluid to flush interstitial fluid and clear metabolic waste; these processes seem to increase during sleep.

  • The relative importance of different drainage routes from perivascular spaces in humans remains to be determined.

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Fig. 1: Perivascular spaces visualized with MRI in humans.
Fig. 2: High-field and conventional MRI of perivascular spaces in humans in vivo.
Fig. 3: Perivascular spaces and small vessel disease.
Fig. 4: Relationship of perivascular spaces to arterioles and venules in humans.
Fig. 5: Uptake of cerebrospinal fluid tracer into perivascular spaces in the whole rat brain visualized by optimal mass transport.
Fig. 6: Anatomy of perivascular spaces around basal and cortical perforating arterioles.
Fig. 7: Uptake of cerebrospinal fluid into perivascular spaces in rodents and humans.
Fig. 8: Movement of fluid in perivascular spaces.

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References

  1. Woollam, D. H. & Millen, J. W. The perivascular spaces of the mammalian central nervous system and their relation to the perineuronal and subarachnoid spaces. J. Anat. 89, 193–200 (1955).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Smith, A. J., Yao, X., Dix, J. A., Jin, B. J. & Verkman, A. S. Test of the ‘glymphatic’ hypothesis demonstrates diffusive and aquaporin-4-independent solute transport in rodent brain parenchyma. eLife 6, e27679 (2017).

    PubMed  PubMed Central  Google Scholar 

  3. Brown, R. et al. Understanding the role of the perivascular space in cerebral small vessel disease. Cardiovasc. Res. 114, 1462–1473 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Francis, F., Ballerini, L. & Wardlaw, J. M. Perivascular spaces and their associations with risk factors, clinical disorders and neuroimaging features: a systematic review and meta-analysis. Int. J. Stroke 14, 359–371 (2019).

    PubMed  Google Scholar 

  5. Debette, S., Schilling, S., Duperron, M., Larsson, S. & Markus, H. Clinical significance of magnetic resonance imaging markers of vascular brain injury: a systematic review and meta-analysis. JAMA Neurol. 76, 81–94 (2018).

    PubMed Central  Google Scholar 

  6. Kwee, R. M. & Kwee, T. C. Virchow-Robin spaces at MR imaging. Radiographics 27, 1071–1086 (2007).

    PubMed  Google Scholar 

  7. Gao, F. et al. Does variable progression of incidental white matter hyperintensities in Alzhiemer’s disease relate to venous insufficiency? Alzheimers Dement. 4, T368–T369 (2009).

    Google Scholar 

  8. Hladky, S. B. & Barrand, M. A. Mechanisms of fluid movement into, through and out of the brain: evaluation of the evidence. Fluids Barriers CNS 11, 26 (2014).

    PubMed  PubMed Central  Google Scholar 

  9. Weller, R. O., Djuanda, E., Yow, H. Y. & Carare, R. O. Lymphatic drainage of the brain and the pathophysiology of neurological disease. Acta Neuropathol. 117, 1–14 (2009).

    CAS  PubMed  Google Scholar 

  10. Bakker, E. N. et al. Lymphatic clearance of the brain: perivascular, paravascular and significance for neurodegenerative diseases. Cell Mol. Neurobiol. 36, 181–194 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Absinta, M. et al. Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI. eLife 6, e29738 (2017).

    PubMed  PubMed Central  Google Scholar 

  12. Xie, L. et al. Sleep drives metabolite clearance from the adult brain. Science 342, 373–377 (2013).

    CAS  PubMed  Google Scholar 

  13. Plog, B. A. & Nedergaard, M. The glymphatic system in central nervous system health and disease: past, present, and future. Ann. Rev. Pathol. 13, 379–394 (2018).

    CAS  Google Scholar 

  14. Bedussi, B. et al. Paravascular channels, cisterns, and the subarachnoid space in the rat brain: a single compartment with preferential pathways. J. Cereb. Blood Flow Metab. 37, 1374–1385 (2017).

    PubMed  Google Scholar 

  15. Ballerini, L. et al. Application of the ordered logit model to optimising Frangi filter parameters for segmentation of perivascular spaces. Procedia Comput. Sci. 90, 61–67 (2016).

    Google Scholar 

  16. Ballerini, L. et al. Perivascular spaces segmentation in brain MRI using optimal 3D filtering. Sci. Rep. 8, 2132 (2018).

    PubMed  PubMed Central  Google Scholar 

  17. Weller, R. O., Hawkes, C. A., Kalaria, R. N., Werring, D. J. & Carare, R. O. White matter changes in dementia: role of impaired drainage of interstitial fluid. Brain Pathol. 25, 63–78 (2015).

    PubMed  Google Scholar 

  18. Tarasoff-Conway, J. M. et al. Clearance systems in the brain — implications for Alzheimer disease. Nat. Rev. Neurol. 11, 457–470 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Durand-Fardel, M. Memoire sur une alteration particuliere de la substance cerebrale [French]. Gaz. Med. Paris. 10, 23–38 (1842).

    Google Scholar 

  20. Fisher, C. M. Lacunar strokes and infarcts: a review. Neurology 32, 871 (1982).

    CAS  PubMed  Google Scholar 

  21. Weed, L. Studies on cerebro-spinal fluid. No. II: the theories of drainage of cerebro-spinal fluid with an analysis of the methods of investigation. J. Med. Res. 31, 21 (1914).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Weed, L. Studies on cerebro-spinal fluid. No. III: The pathways of escape from the subarachnoid spaces with particular reference to the arachnoid villi. J. Med. Res. 31, 51–91 (1914).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Weed, L. The absorption of cerebrospinal fluid into the venous system. Am. J. Anat. 31, 191–221 (1923).

    CAS  Google Scholar 

  24. Nedergaard, M., Iliff, J. J., Benveniste, H. & Deane, R. Methods for evaluating brain-wide paravascular pathway for waste clearance function and methods for treating neurodegenerative disorders based thereon. US Patent 9901650 (2018).

  25. Rasmussen, M. K., Mestre, H. & Nedergaard, M. The glymphatic pathway in neurological disorders. Lancet Neurol. 17, 1016–1024 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Barua, N. U. et al. Intrastriatal convection-enhanced delivery results in widespread perivascular distribution in a pre-clinical model. Fluids Barriers CNS 9, 2 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Braffman, B. H. et al. Brain MR: pathologic correlation with gross and histopathology. 1. Lacunar infarction and Virchow-Robin spaces. AJR Am. J. Roentgenol. 151, 551–558 (1988).

    CAS  PubMed  Google Scholar 

  28. Zhu, Y. C. et al. High degree of dilated Virchow-Robin spaces on MRI is associated with increased risk of dementia. J. Alzheimers Dis. 22, 663–672 (2010).

    PubMed  Google Scholar 

  29. Ferguson, S. C. et al. Cognitive ability and brain structure in type 1 diabetes: relation to microangiopathy and preceding severe hypoglycaemia. Diabetes 52, 149–156 (2003).

    CAS  PubMed  Google Scholar 

  30. MacLullich, A. M. et al. Enlarged perivascular spaces are associated with cognitive function in healthy elderly men. J. Neurol. Neurosurg. Psychiatry 75, 1519–1523 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Patankar, T. F. et al. Dilatation of the Virchow-Robin space is a sensitive indicator of cerebral microvascular disease: study in elderly patients with dementia. AJNR Am. J. Neuroradiol. 26, 1512–1520 (2005).

    PubMed  PubMed Central  Google Scholar 

  32. Kress, B. T. et al. Impairment of paravascular clearance pathways in the aging brain. Ann. Neurol. 76, 845–861 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Iliff, J. J. et al. Brain-wide pathway for waste clearance captured by contrast-enhanced MRI. J. Clin. Invest. 123, 1299–1309 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Elkin, R. et al. in International Conference on Medical Image Computing and Computer-Assisted Intervention. 844–852 (MICCAI, 2018).

  35. Ratner, V. et al. Cerebrospinal and interstitial fluid transport via the glymphatic pathway modeled by optimal mass transport. Neuroimage 152, 530–537 (2017).

    PubMed  Google Scholar 

  36. Humphreys, C. A. et al. A protocol for precise comparisons of small vessel disease lesions between ex vivo magnetic resonance and histopathology. Int. J. Stroke 14, 310–320 (2019).

    PubMed  Google Scholar 

  37. Kiviniemi, V. et al. Ultra-fast magnetic resonance encephalography of physiological brain activity — glymphatic pulsation mechanisms? J. Cereb. Blood Flow. Metab. 36, 1033–1045 (2016).

    CAS  PubMed  Google Scholar 

  38. Shi, Y. et al. Small vessel disease is associated with altered cerebrovascular pulsatility but not resting cerebral blood flow. J. Cereb. Blood Flow. Metab. 40 85–99 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Mestre, H. et al. Flow of cerebrospinal fluid is driven by arterial pulsations and is reduced in hypertension. Nat. Comms 9, 4878 (2018).

    Google Scholar 

  40. Benveniste, H. et al. The glymphatic system and waste clearance with brain aging: a review. Gerontology 65, 106–119 (2018).

    PubMed  Google Scholar 

  41. Bouvy, W. H. et al. Visualization of perivascular spaces and perforating arteries with 7T magnetic resonance imaging. Invest. Radiol. 49, 307–313 (2014).

    PubMed  Google Scholar 

  42. Wuerfel, J. et al. Perivascular spaces — MRI marker of inflammatory activity in the brain? Brain 131, 2332–2340 (2008).

    PubMed  Google Scholar 

  43. Potter, G. M., Chappell, F. M., Morris, Z. & Wardlaw, J. M. Cerebral perivascular spaces visible on magnetic resonance imaging: development of a qualitative rating scale and its observer reliability. Cerebrovasc. Dis. 39, 224–231 (2015).

    PubMed  PubMed Central  Google Scholar 

  44. Zhu, Y. C. et al. Frequency and location of dilated Virchow-Robin spaces in elderly people: a population-based 3D MR imaging study. AJNR Am. J. Neuroradiol. 32, 709–713 (2011).

    PubMed  PubMed Central  Google Scholar 

  45. Yao, M. et al. Dilated perivascular spaces in small-vessel disease: a study in CADASIL. Cerebrovasc. Dis. 37, 155–163 (2014).

    PubMed  Google Scholar 

  46. Potter, G. M. et al. Enlarged perivascular spaces and cerebral small vessel disease. Int. J. Stroke 10, 376–381 (2015).

    PubMed  Google Scholar 

  47. Doubal, F. N., MacLullich, A. M., Ferguson, K. J., Dennis, M. S. & Wardlaw, J. M. Enlarged perivascular spaces on MRI are a feature of cerebral small vessel disease. Stroke 41, 450–454 (2010).

    PubMed  Google Scholar 

  48. Roher, A. E. et al. Cortical and leptomeningeal cerebrovascular amyloid and white matter pathology in Alzheimer’s disease. Mol. Med. 9, 112–122 (2003).

    PubMed  PubMed Central  Google Scholar 

  49. Brown, W. R., Moody, D. M., Challa, V. R., Thore, C. R. & Anstrom, J. A. Venous collagenosis and arteriolar tortuosity in leukoaraiosis. J. Neurol. Sci. 203–204, 159–163 (2002).

    PubMed  Google Scholar 

  50. Vinters, H. V. et al. Review: vascular dementia: clinicopathologic and genetic considerations. Neuropathol. Appl. Neurobiol. 44, 247–266 (2018).

    CAS  PubMed  Google Scholar 

  51. Pettersen, J. A., Keith, J., Gao, F., Spence, J. D. & Black, S. E. CADASIL accelerated by acute hypotension: arterial and venous contribution to leukoaraiosis. Neurology 88, 1077–1080 (2017).

    PubMed  PubMed Central  Google Scholar 

  52. Schlesinger, B. The venous drainage of the brain, with special reference to the Galenic system. Brain 62, 274–291 (1939).

    Google Scholar 

  53. Fisher, E. & Reich, D. S. Imaging new lesions: enhancing our understanding of multiple sclerosis pathogenesis. Neurology 81, 202–203 (2013).

    PubMed  Google Scholar 

  54. Wardlaw, J. M., Dennis, M. S., Warlow, C. P. & Sandercock, P. A. Imaging appearance of the symptomatic perforating artery in patients with lacunar infarction: occlusion or other vascular pathology? Ann. Neurol. 50, 208–215 (2001).

    CAS  PubMed  Google Scholar 

  55. Zhu, Y. C. et al. Severity of dilated Virchow-Robin spaces is associated with age, blood pressure, and MRI markers of small vessel disease: a population-based study. Stroke 41, 2483–2490 (2010).

    PubMed  Google Scholar 

  56. Ramirez, J. et al. Visible Virchow-Robin spaces on magnetic resonance imaging of Alzheimer’s disease patients and normal elderly from the Sunnybrook Dementia Study. J. Alzheimers Dis. 43, 415–424 (2015).

    PubMed  Google Scholar 

  57. Gonzalez-Castro, V. et al. Reliability of an automatic classifier for brain enlarged perivascular spaces burden and comparison with human performance. Clin. Sci. 131, 1465–1481 (2017).

    Google Scholar 

  58. Wardlaw, J. et al. Blood-brain barrier failure as a core mechanism in cerebral small vessel disease and dementia: evidence from a cohort study. Alzheimers Dement. 13, 634–643 (2017).

    PubMed Central  Google Scholar 

  59. Ge, Y., Law, M., Herbert, J. & Grossman, R. I. Prominent perivenular spaces in multiple sclerosis as a sign of perivascular inflammation in primary demyelination. AJNR Am. J. Neuroradiol. 26, 2316–2319 (2005).

    PubMed  PubMed Central  Google Scholar 

  60. Miyata, M. et al. Enlarged perivascular spaces are associated with the disease activity in systemic lupus erythematosus. Sci. Rep. 7, 12566 (2017).

    PubMed  PubMed Central  Google Scholar 

  61. Wiseman, S. J. et al. Cerebral small vessel disease burden is increased in systemic lupus erythematosus. Stroke 47, 2722–2728 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Wiseman, S. J. et al. Cognitive function, disease burden and the structural connectome in systemic lupus erythematosus. Lupus 27, 1329–1337 (2018).

    CAS  PubMed  Google Scholar 

  63. Wiseman, S. J. et al. Fatigue and cognitive function in systemic lupus erythematosus: associations with white matter microstructural damage. A diffusion tensor MRI study and meta-analysis. Lupus 26, 588–597 (2017).

    CAS  PubMed  Google Scholar 

  64. Aribisala, B. S. et al. Circulating inflammatory markers are associated with MR visible perivascular spaces but not directly with white matter hyperintensities. Stroke 45, 605–607 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Lau, K. K. et al. Clinical correlates, ethnic differences, and prognostic implications of perivascular spaces in transient ischemic attack and ischemic stroke. Stroke 48, 1470–1477 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Boulouis, G. et al. Hemorrhage recurrence risk factors in cerebral amyloid angiopathy: comparative analysis of the overall small vessel disease severity score versus individual neuroimaging markers. J. Neurol. Sci. 380, 64–67 (2017).

    PubMed  PubMed Central  Google Scholar 

  67. Gutierrez, J. et al. Brain perivascular spaces as biomarkers of ascular risk: results from the Northern Manhattan Study. AJNR Am. J. Neuroradiol. 38, 862–867 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Uiterwijk, R. et al. Subjective cognitive failures in patients with hypertension are related to cognitive performance and cerebral microbleeds. Hypertension 64, 653–657 (2014).

    CAS  PubMed  Google Scholar 

  69. Beak, H. W. et al. Prevalence of enlarged perivascular spaces in a memory clinic population. Alzheimers Dement. 11, P146 (2015).

    Google Scholar 

  70. Chen, W., Song, X. & Zhang, Y. Assessment of the Virchow-Robin Spaces in Alzheimer disease, mild cognitive impairment, and normal aging, using high-field MR imaging. AJNR Am. J. Neuroradiol. 32, 1490–1495 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Ding, J. et al. Large perivascular spaces visible on magnetic resonance imaging, cerebral small vessel disease progression, and risk of dementia: the age, gene/environment susceptibility–Reykjavik study. JAMA Neurol. 74, 1105–1112 (2017).

    PubMed  PubMed Central  Google Scholar 

  72. Hilal, S. et al. Enlarged perivascular spaces and cognition: a meta-analysis of 5 population-based studies. Neurology 91, e832–e842 (2018).

    PubMed  PubMed Central  Google Scholar 

  73. Lanfranconi, S. & Markus, H. S. COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. Stroke 41, e513–e518 (2010).

    PubMed  Google Scholar 

  74. Fazekas, F., Chawluk, J. B., Alavi, A., Hurtig, H. I. & Zimmerman, R. A. MR signal abnormalities at 1.5T in Alzheimer’s dementia and normal aging. Am. J. Roentgenol. 149, 351–356 (1987).

    CAS  Google Scholar 

  75. Vermeer, S. E. et al. Silent brain infarcts and the risk of dementia and cognitive decline. N. Engl. J. Med. 348, 1215–1222 (2003).

    PubMed  Google Scholar 

  76. Mohr, J. P. et al. The Harvard cooperative stroke registry: a prospective registry. Neurology 28, 754–762 (1978).

    CAS  PubMed  Google Scholar 

  77. Fazekas, F. et al. The frequency of punctate areas of signal loss (microbleeds) on gradient-echo T2*-weighted magnetic resonance imaging of the brain in healthy elderly normals: the Austrian stroke prevention study. J. Neurol. 345, 8 (1998).

    Google Scholar 

  78. Staals, J. et al. Total MRI load of cerebral small vessel disease and cognitive ability in older people. Neurobiol. Aging 36, 2806–2811 (2015).

    PubMed  PubMed Central  Google Scholar 

  79. Valdes Hernandez, M. C., Piper, R. J., Wang, X., Deary, I. J. & Wardlaw, J. M. Towards the automatic computational assessment of enlarged perivascular spaces on brain magnetic resonance images: a systematic review. J. Magn. Reson. Imaging 38, 774–785 (2013).

    Google Scholar 

  80. Pollock, H., Hutchings, M., Weller, R. O. & Zhang, E.-T. Perivascular spaces in the basal gangli of the human brain: their relationship to lacunes. J. Anat. 191, 337–346 (1997).

    PubMed  PubMed Central  Google Scholar 

  81. Wardlaw, J. M., Smith, C. & Dichgans, M. Small vessel disease: mechanisms and clinical implications. Lancet Neurol. 18, 684–696 (2019).

    PubMed  Google Scholar 

  82. Charidimou, A. et al. White matter perivascular spaces: an MRI marker in pathology-proven cerebral amyloid angiopathy? Neurology 82, 57–62 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Keable, A. et al. Deposition of amyloid beta in the walls of human leptomeningeal arteries in relation to perivascular drainage pathways in cerebral amyloid angiopathy. Biochim. Biophys. Acta 1862, 1037–1046 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Wardlaw, J. M. et al. Lacunar stroke is associated with diffuse blood-brain barrier dysfunction. Ann. Neurol. 65, 194–202 (2009).

    PubMed  Google Scholar 

  85. Nation, D. A. et al. Blood–brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nat. Med. 25, 270–276 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Zhang, E. T., Inman, C. B. & Weller, R. O. Interrelationships of the pia mater and the perivascular (Virchow-Robin) spaces in the human cerebrum. J. Anat. 170, 111–123 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Rennels, M. L., Gregory, T. F., Blaumanis, O. R., Fujimoto, K. & Grady, P. A. 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 (1985).

    CAS  PubMed  Google Scholar 

  88. Tithof, J., Kelley, D. H., Mestre, H., Nedergaard, M. & Thomas, J. H. Hydraulic resistance of perivascular spaces in the brain. bioRxiv, https://doi.org/10.1101/522409 (2019).

  89. Iliff, J. J. et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci. Transl. Med. 4, 147ra111 (2012).

    PubMed  PubMed Central  Google Scholar 

  90. Eide, P., Vatnehol, S., Emblem, K. & Ringstad, G. Magnetic resonance imaging provides evidence of glymphatic drainage from human brain to cervical lymph nodes. Sci. Rep. 8, 7194 (2018).

    PubMed  PubMed Central  Google Scholar 

  91. Ringstad, G. et al. Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. JCI Insight 3, e121537 (2018).

    PubMed Central  Google Scholar 

  92. Ringstad, G., Vatnehol, S. & Eide, P. Glymphatic MRI in idiopathic normal pressure hydrocephalus. Brain 140, 2691–2705 (2017).

    PubMed  PubMed Central  Google Scholar 

  93. Lee, H. et al. The effect of body posture on brain glymphatic transport. J. Neurosci. 35, 11034–11044 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Bechter, K. & Schmitz, B. Cerebrospinal fluid outflow along lumbar nerves and possible relevance for pain research: case report and review. Croatian Med. J. 55, 399–404 (2014).

    Google Scholar 

  95. Jessen, N. A., Munk, A. S., Lundgaard, I. & Nedergaard, M. The glymphatic system: a beginner’s guide. Neurochem. Res. 40, 2583–2599 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Thrane, V. et al. Paravascular microcirculation facilitates rapid lipid transport and astrocyte signaling in the brain. Sci. Rep. 3, 2582 (2013).

    PubMed  PubMed Central  Google Scholar 

  97. Morris, A. W. J. et al. Vascular basement membranes as pathways for the passage of fluid into and out of the brain. Acta Neuropathol. 131, 725–736 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Albargothy, N. et al. Convective influx/glymphatic system: tracers injected into the CSF enter and leave the brain along separate periarterial basement membrane pathways. Acta Neuropathol. 136, 139–152 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Hablitz, L. et al. Increased glymphatic influx is correlated with high EEG delta power and low heart rate in mice under anesthesia. Sci. Adv. 5, eaav5447 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Louveau, A. et al. Structural and functional features of central nervous system lymphatic vessels. Nature 523, 337–341 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Aspelund, A. et al. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J. Exp. Med. 212, 991–999 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Ha, S.-K., Nair, G., Absinta, M., Luciano, N. & Reich, D. Magnetic resonance imaging and histopathological visualization of human dural lymphatic vessels. Bio Protoc. 8, e2819 (2018).

    PubMed  PubMed Central  Google Scholar 

  103. Cai, R. et al. Panoptic imaging of transparent mice reveals whole-body neuronal projections and skull-meninges connections. Nat. Neurosci. 22, 317–327 (2019).

    CAS  PubMed  Google Scholar 

  104. Johnston, M., Zakharov, A., Papaiconomou, C., Salmasi, G. & Armstrong, D. Evidence of connections between cerebrospinal fluid and nasal lymphatic vessels in humans, non-human primates and other mammalian species. Cerebrospinal Fluid Res. 1, 2–2 (2004).

    PubMed  PubMed Central  Google Scholar 

  105. De Leon, M. et al. Cerebrospinal fluid clearance in Alzheimer disease measured with dynamic PET. J. Nucl. Med. 58, 1471–1476 (2017).

    PubMed  PubMed Central  Google Scholar 

  106. Iliff, J. J. et al. Cerebral arterial pulsation drives paravascular CSF-interstitial fluid exchange in the murine brain. J. Neurosci. 33, 18190–18199 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Eide, P. K. & Ringstad, G. Delayed clearance of cerebrospinal fluid tracer from entorhinal cortex in idiopathic normal pressure hydrocephalus: a glymphatic magnetic resonance imaging study. J. Cereb. Blood Flow Metab. 39, 1355–1368 (2018).

    PubMed  PubMed Central  Google Scholar 

  108. Montagne, A. et al. Pericyte degeneration causes white matter dysfunction in the mouse central nervous system. Nat. Med. 24, 326–337 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Sweeney, M. D., Sagare, A. P. & Zlokovic, B. V. Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat. Rev. Neurol. 14, 133–150 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Ghosh, M. et al. Pericytes are involved in the pathogenesis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Ann. Neurol. 78, 887–900 (2015).

    CAS  PubMed  Google Scholar 

  111. Dreha-Kulaczewski, S. et al. Inspiration is the major regulator of human CSF flow. J. Neurosci. 35, 2485–2491 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Blair, G. et al. Intracranial functional haemodynamic relationships in patients with cerebral small vessel disease. bioRxiv, 572818, https://doi.org/10.1101/572818 (2019).

  113. Dreha-Kulaczewski, S. et al. Identification of the upward movement of human CSF in vivo and its relation to the brain venous system. J. Neurosci. 37, 2395–2402 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Song, T. J. et al. Moderate-to-severe obstructive sleep apnea is associated with cerebral small vessel disease. Sleep Med. 30, 36–42 (2017).

    PubMed  Google Scholar 

  115. Berezuk, C. et al. Virchow-Robin spaces: correlations with polysomnography-derived sleep parameters. Sleep 38, 853–858 (2015).

    PubMed  PubMed Central  Google Scholar 

  116. Del Brutto, O. H., Mera, R. M., Del Brutto, V. J. & Castillo, P. R. Enlarged basal ganglia perivascular spaces and sleep parameters. A population-based study. Clin. Neurol. Neurosurg. 182, 53–57 (2019).

    PubMed  Google Scholar 

  117. Shokri-Kojori, E. et al. β-Amyloid accumulation in the human brain after one night of sleep deprivation. Proc. Natl Acad Sci. USA 115, 4483–4488 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Ju, Y. S. et al. Slow wave sleep disruption increases cerebrospinal fluid amyloid-beta levels. Brain 140, 2104–2111 (2017).

    PubMed  PubMed Central  Google Scholar 

  119. Holth, J. K. et al. The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans. Science 363, 880–884 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Deane, R. et al. LRP/amyloid β-peptide interaction mediates differential brain efflux of Aβ isoforms. Neuron 43, 333–344 (2004).

    CAS  PubMed  Google Scholar 

  121. Deane, R. et al. apoE isoform-specific disruption of amyloid β peptide clearance from mouse brain. J. Clin. Invest. 118, 4002–4013 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Holter, K. E. et al. Interstitial solute transport in 3D reconstructed neuropil occurs by diffusion rather than bulk flow. Proc. Natl Acad. Sci. USA 114, 9894–9899 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Spector, R., Robert Snodgrass, S. & Johanson, C. E. A balanced view of the cerebrospinal fluid composition and functions: focus on adult humans. Exp. Neurol. 273, 57–68 (2015).

    CAS  PubMed  Google Scholar 

  124. Asgari, M., de Zélicourt, D. & Kurtcuoglu, V. Glymphatic solute transport does not require bulk flow. Sci. Rep. 6, 38635–38635 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Jin, B. J., Smith, A. J. & Verkman, A. S. Spatial model of convective solute transport in brain extracellular space does not support a “glymphatic” mechanism. J. Gen. Physiol. 148, 489–501 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Mestre, H. et al. Aquaporin-4-dependent glymphatic solute transport in the rodent brain. eLife 7, e40070 (2018).

    PubMed  PubMed Central  Google Scholar 

  127. Chen, A. et al. Frontal white matter hyperintensities, clasmatodendrosis and gliovascular abnormalities in ageing and post-stroke dementia. Brain 139, 242–258 (2016).

    PubMed  Google Scholar 

  128. Hasan–Olive, M. M., Enger, R., Hansson, H. A., Nagelhus, E. A. & Eide, P. K. Loss of perivascular aquaporin-4 in idiopathic normal pressure hydrocephalus. Glia 67, 91–100 (2019).

    PubMed  Google Scholar 

  129. Shi, Y. et al. Cerebral blood flow in small vessel disease: a systematic review and meta-analysis. J. Cereb. Blood Flow. Metab. 36, 1653–1667 (2016).

    PubMed  PubMed Central  Google Scholar 

  130. Hawkes, C. A. et al. Perivascular drainage of solutes is impaired in the ageing mouse brain and in the presence of cerebral amyloid angiopathy. Acta Neuropathol. 121, 431–443 (2011).

    PubMed  Google Scholar 

  131. Zeppenfeld, D. M. et al. Association of perivascular localization of aquaporin-4 with cognition and Alzheimer disease in aging brains. JAMA Neurol. 74, 91–99 (2017).

    PubMed  Google Scholar 

  132. Simon, M. J. et al. Transcriptional network analysis of human astrocytic endfoot genes reveals region-specific associations with dementia status and tau pathology. Sci. Rep. 8, 12389 (2018).

    PubMed  PubMed Central  Google Scholar 

  133. Watts, R., Steinklein, J. M., Waldman, L., Zhou, X. & Filippi, C. G. Measuring glymphatic flow in man using quantitative contrast-enhanced MRI. Am. J. Neuroradiol. 40, 648–651 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Bradbury, M. W., Cserr, H. F. & Westrop, R. J. Drainage of cerebral interstitial fluid into deep cervical lymph of the rabbit. Am. J. Physiol. 240, F329–F336 (1981).

    CAS  PubMed  Google Scholar 

  135. Rainey-Smith, S. R. et al. Genetic variation in aquaporin-4 moderates the relationship between sleep and brain Aβ-amyloid burden. Transl. Psychiatry 8, 47 (2018).

    PubMed  PubMed Central  Google Scholar 

  136. Yang, L. et al. Evaluating glymphatic pathway function utilizing clinically relevant intrathecal infusion of CSF tracer. J. Transl. Med. 11, 107 (2013).

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors acknowledge the Fondation Leducq Transatlantic Network of Excellence for the Study of Perivascular Spaces in Small Vessel Disease (grant reference 16 CVD 05). F.N.D. is supported by a Garfield Weston Stroke Association Fellowship and an NHS Research Fellowship from the Scottish Government.

Review criteria

We searched the literature from the mid-1800s to the present for papers on ‘perivascular spaces’, ‘glymphatics’, ‘Virchow–Robin spaces’, ‘small vessel disease’, ‘cerebrospinal fluid’, ‘cerebral blood flow’, ‘white matter hyperintensities’, ‘lacunes’, ‘microbleeds’, ‘siderosis’, ‘stroke’, ‘dementia’, ‘cognition’, ‘magnetic resonance imaging’, ‘2-photon imaging’, ‘electron microscopy’ and ‘immunohistochemistry’. Where available, we used recent systematic reviews and updated their contents. We looked for additional relevant papers in reference lists of review articles and research papers. Our approach was not systematic owing to the breadth of the field, but we aimed to capture key papers in the field. We discussed and debated at length the historical and recent findings in our Leducq research network.

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J.M.W. searched the literature and drafted the paper. H.B., M.N., B.V.Z., H.M., F.N.D., J.R., A.T., R.L.R., D.B., M.S. and A.M. provided additional text, figures or references. H.B., M.N., B.V.Z., H.M., H.L., A.J., S.E.B., F.N.B., R.B., J.R., B.J.M., A.T., L.B., R.L.R., D.B., M.S., A.M., S.C. and K.J.S. all commented on and edited the text. All authors approved the submitted version.

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Correspondence to Joanna M. Wardlaw.

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The authors declare support from academic grants but have no other competing interests. The authors’ institutions receive grant support related to the work described in the paper from the Fondation Leducq (16 CVD 05), the USA National Institutes of Health, the UK Medical Research Council, Stroke Association, Alzheimer’s Society, and Row Fogo Charitable Trust.

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Nature Reviews Neurology thanks R. Carare, A. Charidimou and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

Fondation Leducq Transatlantic Network of Excellence on the Role of the Perivascular Space in Cerebral Small Vessel Disease: www.small-vessel-disease.org

Harmonising Brain Imaging Methods for Vascular Contributions to Neurodegeneration (HARNESS): https://harness-neuroimaging.org/

Supplementary information

Glossary

Perivascular spaces

Spaces or potential spaces around arterioles, capillaries and venules in the brain, along which fluid or particles can pass; not restricted to Virchow–Robin spaces.

Virchow–Robin spaces

Macroscopic spaces, originally identified in postmortem brain specimens, surrounding the perforating vessels in the basal ganglia and hemispheric white matter; thought to correspond to the perivascular spaces that are visible on brain MRI.

Optimal mass transport

(OMT). A method of analysing the passage of a fluid (for example, contrast agent) though a volume (for example, the intracranial cavity).

Lacunes

Small holes in the deep grey or white matter, often the sequelae of a small deep lacunar infarct but commonly found in persons with no prior symptoms; increases with age, associated with cognitive decline, part of the spectrum of small vessel disease.

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Wardlaw, J.M., Benveniste, H., Nedergaard, M. et al. Perivascular spaces in the brain: anatomy, physiology and pathology. Nat Rev Neurol 16, 137–153 (2020). https://doi.org/10.1038/s41582-020-0312-z

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