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.
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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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).
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).
Brown, R. et al. Understanding the role of the perivascular space in cerebral small vessel disease. Cardiovasc. Res. 114, 1462–1473 (2018).
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).
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).
Kwee, R. M. & Kwee, T. C. Virchow-Robin spaces at MR imaging. Radiographics 27, 1071–1086 (2007).
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).
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).
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).
Bakker, E. N. et al. Lymphatic clearance of the brain: perivascular, paravascular and significance for neurodegenerative diseases. Cell Mol. Neurobiol. 36, 181–194 (2016).
Absinta, M. et al. Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI. eLife 6, e29738 (2017).
Xie, L. et al. Sleep drives metabolite clearance from the adult brain. Science 342, 373–377 (2013).
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).
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).
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).
Ballerini, L. et al. Perivascular spaces segmentation in brain MRI using optimal 3D filtering. Sci. Rep. 8, 2132 (2018).
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).
Tarasoff-Conway, J. M. et al. Clearance systems in the brain — implications for Alzheimer disease. Nat. Rev. Neurol. 11, 457–470 (2015).
Durand-Fardel, M. Memoire sur une alteration particuliere de la substance cerebrale [French]. Gaz. Med. Paris. 10, 23–38 (1842).
Fisher, C. M. Lacunar strokes and infarcts: a review. Neurology 32, 871 (1982).
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).
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).
Weed, L. The absorption of cerebrospinal fluid into the venous system. Am. J. Anat. 31, 191–221 (1923).
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).
Rasmussen, M. K., Mestre, H. & Nedergaard, M. The glymphatic pathway in neurological disorders. Lancet Neurol. 17, 1016–1024 (2018).
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).
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).
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).
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).
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).
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).
Kress, B. T. et al. Impairment of paravascular clearance pathways in the aging brain. Ann. Neurol. 76, 845–861 (2014).
Iliff, J. J. et al. Brain-wide pathway for waste clearance captured by contrast-enhanced MRI. J. Clin. Invest. 123, 1299–1309 (2013).
Elkin, R. et al. in International Conference on Medical Image Computing and Computer-Assisted Intervention. 844–852 (MICCAI, 2018).
Ratner, V. et al. Cerebrospinal and interstitial fluid transport via the glymphatic pathway modeled by optimal mass transport. Neuroimage 152, 530–537 (2017).
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).
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).
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).
Mestre, H. et al. Flow of cerebrospinal fluid is driven by arterial pulsations and is reduced in hypertension. Nat. Comms 9, 4878 (2018).
Benveniste, H. et al. The glymphatic system and waste clearance with brain aging: a review. Gerontology 65, 106–119 (2018).
Bouvy, W. H. et al. Visualization of perivascular spaces and perforating arteries with 7T magnetic resonance imaging. Invest. Radiol. 49, 307–313 (2014).
Wuerfel, J. et al. Perivascular spaces — MRI marker of inflammatory activity in the brain? Brain 131, 2332–2340 (2008).
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).
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).
Yao, M. et al. Dilated perivascular spaces in small-vessel disease: a study in CADASIL. Cerebrovasc. Dis. 37, 155–163 (2014).
Potter, G. M. et al. Enlarged perivascular spaces and cerebral small vessel disease. Int. J. Stroke 10, 376–381 (2015).
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).
Roher, A. E. et al. Cortical and leptomeningeal cerebrovascular amyloid and white matter pathology in Alzheimer’s disease. Mol. Med. 9, 112–122 (2003).
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).
Vinters, H. V. et al. Review: vascular dementia: clinicopathologic and genetic considerations. Neuropathol. Appl. Neurobiol. 44, 247–266 (2018).
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).
Schlesinger, B. The venous drainage of the brain, with special reference to the Galenic system. Brain 62, 274–291 (1939).
Fisher, E. & Reich, D. S. Imaging new lesions: enhancing our understanding of multiple sclerosis pathogenesis. Neurology 81, 202–203 (2013).
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).
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).
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).
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).
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).
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).
Miyata, M. et al. Enlarged perivascular spaces are associated with the disease activity in systemic lupus erythematosus. Sci. Rep. 7, 12566 (2017).
Wiseman, S. J. et al. Cerebral small vessel disease burden is increased in systemic lupus erythematosus. Stroke 47, 2722–2728 (2016).
Wiseman, S. J. et al. Cognitive function, disease burden and the structural connectome in systemic lupus erythematosus. Lupus 27, 1329–1337 (2018).
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).
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).
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).
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).
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).
Uiterwijk, R. et al. Subjective cognitive failures in patients with hypertension are related to cognitive performance and cerebral microbleeds. Hypertension 64, 653–657 (2014).
Beak, H. W. et al. Prevalence of enlarged perivascular spaces in a memory clinic population. Alzheimers Dement. 11, P146 (2015).
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).
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).
Hilal, S. et al. Enlarged perivascular spaces and cognition: a meta-analysis of 5 population-based studies. Neurology 91, e832–e842 (2018).
Lanfranconi, S. & Markus, H. S. COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. Stroke 41, e513–e518 (2010).
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).
Vermeer, S. E. et al. Silent brain infarcts and the risk of dementia and cognitive decline. N. Engl. J. Med. 348, 1215–1222 (2003).
Mohr, J. P. et al. The Harvard cooperative stroke registry: a prospective registry. Neurology 28, 754–762 (1978).
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).
Staals, J. et al. Total MRI load of cerebral small vessel disease and cognitive ability in older people. Neurobiol. Aging 36, 2806–2811 (2015).
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).
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).
Wardlaw, J. M., Smith, C. & Dichgans, M. Small vessel disease: mechanisms and clinical implications. Lancet Neurol. 18, 684–696 (2019).
Charidimou, A. et al. White matter perivascular spaces: an MRI marker in pathology-proven cerebral amyloid angiopathy? Neurology 82, 57–62 (2014).
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).
Wardlaw, J. M. et al. Lacunar stroke is associated with diffuse blood-brain barrier dysfunction. Ann. Neurol. 65, 194–202 (2009).
Nation, D. A. et al. Blood–brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nat. Med. 25, 270–276 (2019).
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).
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).
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).
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).
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).
Ringstad, G. et al. Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. JCI Insight 3, e121537 (2018).
Ringstad, G., Vatnehol, S. & Eide, P. Glymphatic MRI in idiopathic normal pressure hydrocephalus. Brain 140, 2691–2705 (2017).
Lee, H. et al. The effect of body posture on brain glymphatic transport. J. Neurosci. 35, 11034–11044 (2015).
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).
Jessen, N. A., Munk, A. S., Lundgaard, I. & Nedergaard, M. The glymphatic system: a beginner’s guide. Neurochem. Res. 40, 2583–2599 (2015).
Thrane, V. et al. Paravascular microcirculation facilitates rapid lipid transport and astrocyte signaling in the brain. Sci. Rep. 3, 2582 (2013).
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).
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).
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).
Louveau, A. et al. Structural and functional features of central nervous system lymphatic vessels. Nature 523, 337–341 (2015).
Aspelund, A. et al. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J. Exp. Med. 212, 991–999 (2015).
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).
Cai, R. et al. Panoptic imaging of transparent mice reveals whole-body neuronal projections and skull-meninges connections. Nat. Neurosci. 22, 317–327 (2019).
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).
De Leon, M. et al. Cerebrospinal fluid clearance in Alzheimer disease measured with dynamic PET. J. Nucl. Med. 58, 1471–1476 (2017).
Iliff, J. J. et al. Cerebral arterial pulsation drives paravascular CSF-interstitial fluid exchange in the murine brain. J. Neurosci. 33, 18190–18199 (2013).
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).
Montagne, A. et al. Pericyte degeneration causes white matter dysfunction in the mouse central nervous system. Nat. Med. 24, 326–337 (2018).
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).
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).
Dreha-Kulaczewski, S. et al. Inspiration is the major regulator of human CSF flow. J. Neurosci. 35, 2485–2491 (2015).
Blair, G. et al. Intracranial functional haemodynamic relationships in patients with cerebral small vessel disease. bioRxiv, 572818, https://doi.org/10.1101/572818 (2019).
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).
Song, T. J. et al. Moderate-to-severe obstructive sleep apnea is associated with cerebral small vessel disease. Sleep Med. 30, 36–42 (2017).
Berezuk, C. et al. Virchow-Robin spaces: correlations with polysomnography-derived sleep parameters. Sleep 38, 853–858 (2015).
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).
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).
Ju, Y. S. et al. Slow wave sleep disruption increases cerebrospinal fluid amyloid-beta levels. Brain 140, 2104–2111 (2017).
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).
Deane, R. et al. LRP/amyloid β-peptide interaction mediates differential brain efflux of Aβ isoforms. Neuron 43, 333–344 (2004).
Deane, R. et al. apoE isoform-specific disruption of amyloid β peptide clearance from mouse brain. J. Clin. Invest. 118, 4002–4013 (2008).
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).
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).
Asgari, M., de Zélicourt, D. & Kurtcuoglu, V. Glymphatic solute transport does not require bulk flow. Sci. Rep. 6, 38635–38635 (2016).
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).
Mestre, H. et al. Aquaporin-4-dependent glymphatic solute transport in the rodent brain. eLife 7, e40070 (2018).
Chen, A. et al. Frontal white matter hyperintensities, clasmatodendrosis and gliovascular abnormalities in ageing and post-stroke dementia. Brain 139, 242–258 (2016).
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).
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).
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).
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).
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).
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).
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).
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).
Yang, L. et al. Evaluating glymphatic pathway function utilizing clinically relevant intrathecal infusion of CSF tracer. J. Transl. Med. 11, 107 (2013).
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.
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.
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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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/
- 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).
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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