Skip to main content

Advertisement

SpringerLink
Log in

Brain Glymphatic/Lymphatic Imaging by MRI and PET

  • Review
  • Published:
Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Since glymphatic was proposed and meningeal lymphatic was discovered, MRI and even PET were introduced to investigate brain parenchymal interstitial fluid (ISF), cerebrospinal fluid (CSF), and lymphatic outflow in rodents and humans. Previous findings by ex vivo fluorescent microscopic, and in vivo two-photon imaging in rodents were reproduced using intrathecal contrast (gadobutrol and the similar)-enhanced MRI in rodents and further in humans. On dynamic MRI of meningeal lymphatics, in contrast to rodents, humans use mainly dorsal meningeal lymphatic pathways of ISF-CSF-lymphatic efflux. In mice, ISF-CSF exchange was examined thoroughly using an intra-cistern injection of fluorescent tracers during sleep, aging, and neurodegeneration yielding many details. CSF to lymphatic efflux is across arachnoid barrier cells over the dorsal dura in rodents and in humans. Meningeal lymphatic efflux to cervical lymph nodes and systemic circulation is also well-delineated especially in humans onintrathecal contrast MRI. Sleep- or anesthesia-related changes of glymphatic-lymphatic flow and the coupling of ISF-CSF-lymphatic drainage are major confounders ininterpreting brain glymphatic/lymphatic outflow in rodents. PET imaging in humans should be interpreted based on human anatomy and physiology, different in some aspects, using MRI recently. Based on the summary in this review, we propose non-invasive and longer-term intrathecal SPECT/PET or MRI studies to unravel the roles of brain glymphatic/lymphatic in diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid. β Sci Transl Med. 2012;4:147ra111.

  2. Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, et al. Structural and functional features of central nervous system lymphatic vessels. Nature. 2015;523:337–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Iliff JJ, Wang M, Zeppenfeld DM, Venkataraman A, Plog BA, Liao Y, et al. Cerebral arterial pulsation drives paravascular CSF-interstitial fluid exchange in the murine brain. J Neurosci. 2013;33:18190–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Aspelund A, Antila S, Proulx ST, Karlsen TV, Karaman S, Detmar M, et al. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J Exp Med. 2015;212:991–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Smith AJ, Yao X, Dix JA, Jin BJ, Verkman AS. Test of the ‘glymphatic’ hypothesis demonstrates diffusive and aquaporin-4-independent solute transport in rodent brain parenchyma. Elife. 2017;6:e27679.

  6. Lei Y, Han H, Yuan F, Javeed A, Zhao Y. The brain interstitial system: anatomy, modeling, in vivo measurement, and applications. Prog Neurobiol. 2017;157:230–46.

    PubMed  Google Scholar 

  7. Mestre H, Hablitz LM, Xavier ALR, Feng W, Zou W, Pu T, et al. Aquaporin-4-dependent glymphatic solute transport in the rodent brain. Elife. 2018;7:e40070.

  8. Nakada T, Kwee IL. Fluid dynamics inside the brain barrier: current concept of interstitial flow, glymphatic flow, and cerebrospinal fluid circulation in the brain. Neuroscientist. 2019;25:155–66.

    PubMed  Google Scholar 

  9. Iliff J, Simon M. CrossTalk proposal: the glymphatic system supports convective exchange of cerebrospinal fluid and brain interstitial fluid that is mediated by perivascular aquaporin-4. J Physiol. 2019;597:4417–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Smith AJ, Verkman AS. CrossTalk opposing view: going against the flow: interstitial solute transport in brain is diffusive and aquaporin-4 independent. J Physiol. 2019;597:4421–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Smith AJ, Verkman AS. Rebuttal from Alex J. Smith and Alan S. Verkman. J Physiol. 2019;597:4427–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Louveau A, Plog BA, Antila S, Alitalo K, Nedergaard M, Kipnis J. Understanding the functions and relationships of the glymphatic system and meningeal lymphatics. J Clin Invest. 2017;127:3210–9.

    PubMed  PubMed Central  Google Scholar 

  13. Raper D, Louveau A, Kipnis J. How do meningeal lymphatic vessels drain the CNS? Trends Neurosci. 2016;39:581–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Antila S, Karaman S, Nurmi H, Airavaara M, Voutilainen MH, Mathivet T, et al. Development and plasticity of meningeal lymphatic vessels. J Exp Med. 2017;214:3645–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Da Mesquita S, Louveau A, Vaccari A, Smirnov I, Cornelison RC, Kingsmore KM, et al. Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease. Nature. 2018;560:185–91.

    PubMed  PubMed Central  Google Scholar 

  16. Frederick N, Louveau A. Meningeal lymphatics, immunity and neuroinflammation. Curr Opin Neurobiol. 2020;62:41–7.

    CAS  PubMed  Google Scholar 

  17. Da Mesquita S, Fu Z, Kipnis J. The meningeal lymphatic system: a new player in neurophysiology. Neuron. 2018;100:375–88.

    PubMed  PubMed Central  Google Scholar 

  18. Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, et al. Sleep drives metabolite clearance from the adult brain. Science (80- ). 2013;342:373–7.

    CAS  Google Scholar 

  19. Kress BT, Iliff JJ, Xia M, Wang M, Wei HS, Zeppenfeld D, et al. Impairment of paravascular clearance pathways in the aging brain. Ann Neurol. 2014;76:845–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Mastorakos P, McGavern D. The anatomy and immunology of vasculature in the central nervous system. Sci Immunol 2019;4:eaav0492.

  21. Coles JA, Myburgh E, Brewer JM, McMenamin PG. Where are we? The anatomy of the murine cortical meninges revisited for intravital imaging, immunology, and clearance of waste from the brain. Prog Neurobiol. 2017;156:107–48.

    PubMed  Google Scholar 

  22. Zhou Y, Cai J, Zhang W, Gong X, Yan S, Zhang K, et al. Impairment of the glymphatic pathway and putative meningeal lymphatic vessels in the aging human. Ann Neurol. 2020;87:357–69.

    CAS  PubMed  Google Scholar 

  23. Castro Dias M, Mapunda JA, Vladymyrov M, Engelhardt B. Structure and junctional complexes of endothelial, epithelial and glial brain barriers. Int J Mol Sci. 2019;20:5372.

  24. Ringstad G, Eide PK. Cerebrospinal fluid tracer efflux to parasagittal dura in humans. Nat Commun. 2020;11:1–9.

    Google Scholar 

  25. Goodman JR, Adham ZO, Woltjer RL, Lund AW, Iliff JJ. Characterization of dural sinus-associated lymphatic vasculature in human Alzheimer’s dementia subjects. Brain Behav Immun. 2018;73:34–40.

    PubMed  PubMed Central  Google Scholar 

  26. Dupont G, Schmidt C, Yilmaz E, Oskouian RJ, Macchi V, de Caro R, et al. Our current understanding of the lymphatics of the brain and spinal cord. Clin Anat. 2019;32:117–21.

    PubMed  Google Scholar 

  27. Ahn JH, Cho H, Kim JH, Kim SH, Ham JS, Park I, et al. Meningeal lymphatic vessels at the skull base drain cerebrospinal fluid. Nature. 2019;572:62–6.

    CAS  PubMed  Google Scholar 

  28. Lüdemann W, von Rautenfeld DB, Samii M, Brinker T. Ultrastructure of the cerebrospinal fluid outflow along the optic nerve into the lymphatic system. Childs Nerv Syst. 2005;21:96–103.

    PubMed  Google Scholar 

  29. Walter BA, Valera VA, Takahashi S, Ushiki T. The olfactory route for cerebrospinal fluid drainage into the peripheral lymphatic system. Neuropathol Appl Neurobiol. 2006;32:388–96.

    CAS  PubMed  Google Scholar 

  30. Ma Q, Ineichen BV, Detmar M, Proulx ST. Outflow of cerebrospinal fluid is predominantly through lymphatic vessels and is reduced in aged mice. Nat Commun. 2017;8:1434.

  31. Wang X, Lou N, Eberhardt A, Yang Y, Kusk P, Xu Q, et al. An ocular glymphatic clearance system removes β-amyloid from the rodent eye. Sci Transl Med. 2020;12:eaaw3210.

  32. Miura M, Kato S, Von Lüdinghausen M. Lymphatic drainage of the cerebrospinal fluid from monkey spinal meninges with special reference to the distribution of the epidural lymphatics. Arch Histol Cytol. 1998;61:277–86.

    CAS  PubMed  Google Scholar 

  33. Clapham R, O’sullivan E, Weller RO, Carare RO. Cervical lymph nodes are found in direct relationship with the internal carotid artery: significance for the lymphatic drainage of the brain. Clin Anat 2009;23:43–47.

  34. Jacob L, Boisserand LSB, Geraldo LHM, de Brito Neto J, Mathivet T, Antila S, et al. Anatomy and function of the vertebral column lymphatic network in mice. Nat Commun. 2019;10:4594.

  35. Kuo PH, Stuehm C, Squire S, Johnson K. Meningeal lymphatic vessel flow runs countercurrent to venous flow in the superior sagittal sinus of the human brain. Tomography. 2018;4:99–104.

    PubMed  PubMed Central  Google Scholar 

  36. Maloveska M, Danko J, Petrovova E, Kresakova L, Vdoviakova K, Michalicova A, et al. Dynamics of Evans blue clearance from cerebrospinal fluid into meningeal lymphatic vessels and deep cervical lymph nodes. Neurol Res. 2018;40:372–80.

    CAS  PubMed  Google Scholar 

  37. Bradbury MW, Cole DF. The role of the lymphatic system in drainage of cerebrospinal fluid and aqueous humour. J Physiol. 1980;299:353–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Boulton M, Flessner M, Armstrong D, Hay J, Johnston M. Determination of volumetric cerebrospinal fluid absorption into extracranial lymphatics in sheep. Am J Physiol - Regul Integr Comp Physiol. 1998;274:R88–96.

    CAS  Google Scholar 

  39. Eide PK, Vatnehol SAS, Emblem KE, Ringstad G. Magnetic resonance imaging provides evidence of glymphatic drainage from human brain to cervical lymph nodes. Sci Rep. 2018;8:7194.

  40. Ma Q, Ries M, Decker Y, Müller A, Riner C, Bücker A, et al. Rapid lymphatic efflux limits cerebrospinal fluid flow to the brain. Acta Neuropathol. 2019;137:151–65.

    PubMed  Google Scholar 

  41. Koh Chang-Soon Nuclear Medicine. Korea; 2008.

  42. Grubb S, Lauritzen M. Deep sleep drives brain fluid oscillations. Science. 2019;366:572–3.

  43. Iadecola C. The neurovascular unit coming of age: a journey through neurovascular coupling in health and disease. Neuron. 2017;96:17–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Matsumae M, Kuroda K, Yatsushiro S, Hirayama A, Hayashi N, Takizawa K, et al. Changing the currently held concept of cerebrospinal fluid dynamics based on shared findings of cerebrospinal fluid motion in the cranial cavity using various types of magnetic resonance imaging techniques. Neurol Med Chir (Tokyo). 2019;59:133–46.

    Google Scholar 

  45. Hirayama A, Matsumae M, Yatsushiro S, Abdulla A, Atsumi H, Kuroda K. Visualization of pulsatile CSF motion around membrane-like structures with both 4D velocity mapping and time-SLIP technique. Magn Reson Med Sci. 2015;14:263–73.

    PubMed  Google Scholar 

  46. Fultz NE, Bonmassar G, Setsompop K, Stickgold RA, Rosen BR, Polimeni JR, et al. Coupled electrophysiological, hemodynamic, and cerebrospinal fluid oscillations in human sleep. Science (80- ). 2019;366:628–31.

    CAS  Google Scholar 

  47. Matsumae M, Hirayama A, Atsumi H, Yatsushiro S, Kuroda K. Velocity and pressure gradients of cerebrospinal fluid assessed with magnetic resonance imaging-clinical article. J Neurosurg. 2014;120:218–27.

    PubMed  Google Scholar 

  48. Murtha LA, Yang Q, Parsons MW, Levi CR, Beard DJ, Spratt NJ, et al. Cerebrospinal fluid is drained primarily via the spinal canal and olfactory route in young and aged spontaneously hypertensive rats. Fluids Barriers CNS. 2014;11:12.

    PubMed  PubMed Central  Google Scholar 

  49. Iliff JJ, Lee H, Yu M, Feng T, Logan J, Nedergaard M, et al. Brain-wide pathway for waste clearance captured by contrast-enhanced MRI. J Clin Invest. 2013;123:1299–309.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Absinta M, Ha SK, Nair G, Sati P, Luciano NJ, Palisoc M, et al. Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI. Elife. 2017;6:e29738.

  51. Watts R, Steinklein JM, Waldman L, Zhou X, Filippi CG. Measuring glymphatic flow in man using quantitative contrast-enhanced MRI. Am J Neuroradiol. 2019;40:648–51.

    CAS  PubMed  Google Scholar 

  52. Suzuki K, Yamada K, Nakada K, Suzuki Y, Watanabe M, Kwee IL, et al. MRI characteristics of the glia limitans externa: a 7T study. Magn Reson Imaging. 2017;44:140–5.

    PubMed  Google Scholar 

  53. Gakuba C, Gaberel T, Goursaud S, Bourges J, D Palma C, Quenault A, et al. General anesthesia inhibits the activity of the “glymphatic system” Theranostics 2018;8:710–722.

  54. Benveniste H, Heerdt PM, Fontes M, Rothman DL, Volkow ND. Glymphatic system function in relation to anesthesia and sleep states. Anesth Analg. 2019;128:747–58.

    PubMed  Google Scholar 

  55. Benveniste H, Lee H, Ding F, Sun Q, Al-Bizri E, Makaryus R, et al. Anesthesia with dexmedetomidine and low-dose isoflurane increases solute transport via the glymphatic pathway in rat brain when compared with high-dose isoflurane. Anesthesiology. 2017;127:976–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Benveniste H, Liu X, Koundal S, Sanggaard S, Lee H, Wardlaw J. The Glymphatic system and waste clearance with brain aging: a review. Gerontology. 2019;65:106–19.

    PubMed  Google Scholar 

  57. Lundgaard I, Lu ML, Yang E, Peng W, Mestre H, Hitomi E, et al. Glymphatic clearance controls state-dependent changes in brain lactate concentration. J Cereb Blood Flow Metab. 2017;37:2112–24.

    CAS  PubMed  Google Scholar 

  58. Lundgaard I, Wang W, Eberhardt A, Vinitsky HS, Reeves BC, Peng S, et al. Beneficial effects of low alcohol exposure, but adverse effects of high alcohol intake on glymphatic function. Sci Rep 2018;8:2246.

  59. Taoka T, Jost G, Frenzel T, Naganawa S, Pietsch H. Impact of the glymphatic system on the kinetic and distribution of gadodiamide in the rat brain. Investig Radiol. 2018;53:529–34.

    CAS  Google Scholar 

  60. Taoka T, Naganawa S. Glymphatic imaging using MRI. J Magn Reson Imaging. 2020;51:11–24.

    PubMed  Google Scholar 

  61. De Leon MJ, Li Y, Okamura N, Tsui WH, Saint-Louis LA, Glodzik L, et al. Cerebrospinal fluid clearance in Alzheimer disease measured with dynamic PET. J Nucl Med. 2017;58:1471–6.

    PubMed  PubMed Central  Google Scholar 

  62. Schubert JJ, Veronese M, Marchitelli L, Bodini B, Tonietto M, Stankoff B, et al. Dynamic 11C-PIB PET shows cerebrospinal fluid flow alterations in Alzheimer disease and multiple sclerosis. J Nucl Med. 2019;60:1452–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Smith AJ, Verkman AS. The “glymphatic” mechanism for solute clearance in Alzheimer’s disease: game changer or unproven speculation? FASEB J. 2018;32:543–51.

    CAS  PubMed  Google Scholar 

  64. Asgari M, De Zélicourt D, Kurtcuoglu V. Glymphatic solute transport does not require bulk flow. Sci Rep. 2016;6:38635.

  65. Kounda S, Elkin R, Nadeem S, Xue Y, Constantinou S, Sanggaard S, et al. Optimal mass transport with Lagrangian workflow reveals advective and diffusion driven solute transport in the glymphatic system. Sci Rep 2020;10:1990.

  66. Cai X, Qiao J, Kulkarni P, Harding IC, Ebong E, Ferris CF. Imaging the effect of the circadian light–dark cycle on the glymphatic system in awake rats. Proc Natl Acad Sci U S A. 2020;117:668–76.

    CAS  PubMed  Google Scholar 

  67. Hablitz LM, Vinitsky HS, Sun Q, Stæger FF, Sigurdsson B, Mortensen KN, et al. Increased glymphatic influx is correlated with high EEG delta power and low heart rate in mice under anesthesia. Sci Adv. 2019;5:eaav5447.

  68. Achariyar TM, Li B, Peng W, Verghese PB, Shi Y, McConnell E, et al. Glymphatic distribution of CSF-derived apoE into brain is isoform specific and suppressed during sleep deprivation. Mol Neurodegener 2016;11:74.

  69. DiNuzzo M, Nedergaard M. Brain energetics during the sleep–wake cycle. Curr Opin Neurobiol. 2017;47:65–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Gandhi GK, Cruz NF, Ball KK, Dienel GA. Astrocytes are poised for lactate trafficking and release from activated brain and for supply of glucose to neurons. J Neurochem. 2009;111:522–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Verkhratsky A, Nedergaard M. Physiology of astroglia. Physiol Rev. 2018;98:239–389.

    CAS  PubMed  Google Scholar 

  72. Brown RE, Basheer R, McKenna JT, Strecker RE, McCarley RW. Control of sleep and wakefulness. Physiol Rev. 2012;92:1087–187.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Cordone S, Annarumma L, Rossini PM, De Gennaro L. Sleep and β-amyloid deposition in Alzheimer disease: insights on mechanisms and possible innovative treatments. Front Pharmacol 2019;10:659.

  74. Ooms S, Overeem S, Besse K, Rikkert MO, Verbeek M, Claassen JAHR. Effect of 1 night of total sleep deprivation on cerebrospinal fluid β-amyloid 42 in healthy middle-aged men a randomized clinical trial. JAMA Neurol. 2014;71:971–7.

    PubMed  Google Scholar 

  75. Shokri-Kojori E, Wang GJ, Wiers CE, Demiral SB, Guo M, Kim SW, et al. β-Amyloid accumulation in the human brain after one night of sleep deprivation. Proc Natl Acad Sci U S A. 2018;115:4483–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Leenaars CHC, Savelyev SA, Van der Mierden S, Joosten RNJMA, Dematteis M, Porkka-Heiskanen T, et al. Intracerebral adenosine during sleep deprivation: a meta-analysis and new experimental data. J Circadian Rhythms. 2018;16:1–11.

    Google Scholar 

  77. Kang JE, Lim MM, Bateman RJ, Lee JJ, Smyth LP, Cirrito JR, et al. Amyloid-β dynamics are regulated by orexin and the sleep-wake cycle. Science. 2009;326(80):1005–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Holth JK, Fritschi SK, Wang C, Pedersen NP, Cirrito JR, Mahan TE, et al. The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans. Science. 2019;363(80):80–884.

    Google Scholar 

  79. Noble W, Spires-Jones TL. Sleep well to slow Alzheimer’s progression? Sleep disruption promotes the spread of damaging tau pathology in Alzheimer’s disease. Science. 2019;363(80):813–4.

    CAS  PubMed  Google Scholar 

  80. Papadopoulos MC, Verkman AS. Aquaporin water channels in the nervous system. Nat Rev Neurosci. 2013;14:265–77.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Haydon PG. Astrocytes and the modulation of sleep. Curr Opin Neurobiol. 2017;44:28–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Ribeiro-Rodrigues TM, Martins-Marques T, Morel S, Kwak BR, Girão H. Role of connexin 43 in different forms of intercellular communication-gap junctions, extracellular vesicles and tunnelling nanotubes. J Cell Sci. 2017;130:3619–30.

    CAS  PubMed  Google Scholar 

  83. Azevedo FAC, Carvalho LRB, Grinberg LT, Farfel JM, Ferretti REL, Leite REP, et al. Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled-up primate brain. J Comp Neurol. 2009;513:532–41.

    PubMed  Google Scholar 

  84. von Bartheld CS, Bahney J, Herculano-Houzel S. The search for true numbers of neurons and glial cells in the human brain: a review of 150 years of cell counting. J Comp Neurol. 2016;524:3865–95.

    Google Scholar 

  85. Triacca V, Güç E, Kilarski WW, Pisano M, Swartz MA. Transcellular pathways in lymphatic endothelial cells regulate changes in solute transport by fluid stress. Circ Res. 2017;120:1440–52.

    CAS  PubMed  Google Scholar 

  86. Berridge CW, Schmeichel BE, España RA. Noradrenergic modulation of wakefulness/arousal. Sleep Med Rev. 2012;16:187–97.

    PubMed  PubMed Central  Google Scholar 

  87. Greene RW, Bjorness TE, Suzuki A. The adenosine-mediated, neuronal-glial, homeostatic sleep response. Curr Opin Neurobiol. 2017;44:236–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Hauglund NL, Pavan C, Nedergaard M. Cleaning the sleeping brain–the potential restorative function of the glymphatic system. Curr Opin Physiol. 2020;15:1–6.

    Google Scholar 

  89. Ries M, Sastre M. Mechanisms of Aβ clearance and degradation by glial cells. Front Aging Neurosci. 2016;8:160.

    PubMed  PubMed Central  Google Scholar 

  90. Zuroff L, Daley D, Black KL, Koronyo-Hamaoui M. Clearance of cerebral Aβ in Alzheimer’s disease: reassessing the role of microglia and monocytes. Cell Mol Life Sci. 2017;74:2167–201.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Yamazaki Y, Zhao N, Caulfield TR, Liu CC, Bu G. Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nat Rev Neurol. 2019;15:501–18.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Shi Y, Holtzman DM. Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight. Nat Rev Immunol. 2018;18:759–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Yeh FL, Hansen DV, Sheng M. TREM2, microglia, and neurodegenerative diseases. Trends Mol Med. 2017;23:512–33.

    CAS  PubMed  Google Scholar 

  94. Hansen DV, Hanson JE, Sheng M. Microglia in Alzheimer’s disease. J Cell Biol. 2018;217:459–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Mathys H, Davila-Velderrain J, Peng Z, Gao F, Mohammadi S, Young JZ, et al. Single-cell transcriptomic analysis of Alzheimer’s disease. Nature. 2019;570:332–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Guo JL, Lee VMY. Cell-to-cell transmission of pathogenic proteins in neurodegenerative diseases. Nat Med. 2014;20:130–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Peng C, Trojanowski JQ, Lee VMY. Protein transmission in neurodegenerative disease. Nat Rev Neurol. 2020;16:199–212.

    CAS  PubMed  Google Scholar 

  98. Vaquer-Alicea J, Diamond MI. Propagation of protein aggregation in neurodegenerative diseases. Annu Rev Biochem. 2019;88:785–810.

    CAS  PubMed  Google Scholar 

  99. Chen XQ, Mobley WC. Alzheimer disease pathogenesis: insights from molecular and cellular biology studies of oligomeric Aβ and tau species. Front Neurosci 2019;13:659.

  100. Canter RG, Penney J, Tsai LH. The road to restoring neural circuits for the treatment of Alzheimer’s disease. Nature. 2016;539:187–96.

    PubMed  Google Scholar 

  101. Španić E, Langer Horvat L, Hof PR, Šimić G. Role of microglial cells in Alzheimer’s disease tau propagation. Front Aging Neurosci. 2019;11:271.

    PubMed  PubMed Central  Google Scholar 

  102. Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017;541:481–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Rothhammer V, Borucki DM, Tjon EC, Takenaka MC, Chao CC, Ardura-Fabregat A, et al. Microglial control of astrocytes in response to microbial metabolites. Nature. 2018;557:724–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Zott B, Simon MM, Hong W, Unger F, Chen-Engerer HJ, Frosch MP, et al. A vicious cycle of β amyloid−dependent neuronal hyperactivation. Science. 2019;365(80):559–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Busche MA, Wegmann S, Dujardin S, Commins C, Schiantarelli J, Klickstein N, et al. Tau impairs neural circuits, dominating amyloid-β effects, in Alzheimer models in vivo. Nat Neurosci. 2019;22:57–64.

    CAS  PubMed  Google Scholar 

  106. Götz J, Bodea LG, Goedert M. Rodent models for Alzheimer disease. Nat Rev Neurosci. 2018;19:583–98.

    PubMed  Google Scholar 

  107. van der Kant R, Goldstein LSB, Ossenkoppele R. Amyloid-β-independent regulators of tau pathology in Alzheimer disease. Nat Rev Neurosci. 2020;21:21–35.

    PubMed  Google Scholar 

  108. Hardy J, De Strooper B. Alzheimer’s disease: where next for anti-amyloid therapies? Brain. 2017;140:853–5.

    PubMed  Google Scholar 

  109. Gauthier S, Alam J, Fillit H, Iwatsubo T, Liu-Seifert H, Sabbagh M, et al. Combination therapy for Alzheimer’s disease: perspectives of the EU/US CTAD Task Force. J Prev Alzheimer’s Dis. 2019;6:164–8.

    CAS  Google Scholar 

  110. Vander Zanden CM, Chi EY. Passive immunotherapies targeting amyloid beta and tau oligomers in Alzheimer’s disease. J Pharm Sci. 2020;109:68–73.

    CAS  PubMed  Google Scholar 

  111. Liu CC, Hu J, Zhao N, Wang J, Wang N, Cirrito JR, et al. Astrocytic LRP1 mediates brain Aβ clearance and impacts amyloid deposition. J Neurosci. 2017;37:4023–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Lee Y, Choi Y, Park E-J, Kwon S, Kim H, Lee JY, et al. Improvement of glymphatic-lymphatic drainage of beta-amyloid by focused ultrasound in Alzheimer’s disease model. bioRxiv 2020; Sci Rep in revision.

  113. Patel TK, Habimana-Griffin L, Gao X, Xu B, Achilefu S, Alitalo K, et al. Dural lymphatics regulate clearance of extracellular tau from the CNS. Mol Neurodegener. 2019;14:11.

    PubMed  PubMed Central  Google Scholar 

  114. Dupont G, Iwanaga J, Yilmaz E, Tubbs RS. Connections between amyloid beta and the meningeal lymphatics as a possible route for clearance and therapeutics. Lymphat Res Biol. 2020;18:2–6.

    PubMed  Google Scholar 

  115. Louveau A, Da Mesquita S, Kipnis J. Lymphatics in neurological disorders: a neuro-Lympho-vascular component of multiple sclerosis and Alzheimer’s disease? Neuron. 2016;91:957–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Romanova L, Philips H, Calip G, Hauser K, Peterson D, Lazarov O, et al. Energy-dependent transport at dural lymphatic vessels is necessary for Aβ brain clearance in Alzheimer’s disease. bioRxiv. 2019;427617.

  117. Yoffey JM, Drinker CK. The lymphatic pathway from the nose and pharynx: the absorption of dyes. J Exp Med. 1938;68:1–12.

  118. Larsen S, Landolt H, Berger W, Nedergaard M, Knudsen G, Holst S. Haplotype of the astrocytic water channel AQP4 modulates slow wave energy in human NREM sleep. PLoS Biology. 2020;18.5:e3000623.

  119. Jordão JF, Thévenot E, Markham-Coultes K, Scarcelli T, Weng YQ, Xhima K, et al. Amyloid-β plaque reduction, endogenous antibody delivery and glial activation by brain-targeted, transcranial focused ultrasound. Exp Neurol. 2013;248:16–29.

    PubMed  PubMed Central  Google Scholar 

  120. Burgess A, Dubey S, Yeung S, Hough O, Eterman N, Aubert I, et al. Alzheimer disease in a mouse model: Mr imaging-guided focused ultrasound targeted to the hippocampus opens the blood-brain barrier and improves pathologic abnormalities and behavior. Radiology. 2014;273:736–45.

    PubMed  PubMed Central  Google Scholar 

  121. Leinenga G, Götz J. Scanning ultrasound removes amyloid-b and restores memory in an Alzheimer’s disease mouse model. Sci Transl Med. 2015;7. 278:278ra33-278ra33.

  122. Poon CT, Shah K, Lin C, Tse R, Kim KK, Mooney S, et al. Time course of focused ultrasound effects on β-amyloid plaque pathology in the TgCRND8 mouse model of Alzheimer’s disease. Sci Rep. 2018;8:1–11.

    CAS  Google Scholar 

  123. Karakatsani ME, Kugelman T, Ji R, Murillo M, Wang S, Niimi Y, et al. Unilateral focused ultrasound-induced blood-brain barrier opening reduces phosphorylated tau from the rTg4510 mouse model. Theranostics. 2019;9:5396–411.

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Pandit R, Leinenga G, Götz J. Repeated ultrasound treatment of tau transgenic mice clears neuronal tau by autophagy and improves behavioral functions. Theranostics. 2019;9:3754–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Meng Y, Abrahao A, Heyn CC, Bethune AJ, Huang Y, Pople CB, et al. Glymphatics visualization after focused ultrasound-induced blood–brain barrier opening in humans. Ann Neurol. 2019;86:975–80.

    CAS  PubMed  Google Scholar 

  126. xu LD, He X, Wu D, Zhang Q, Yang C, yin LF, et al. Continuous theta burst stimulation facilitates the clearance efficiency of the glymphatic pathway in a mouse model of sleep deprivation. Neurosci Lett. 2017;653:189–94.

    PubMed  Google Scholar 

  127. Zeppenfeld DM, Simon M, Haswell JD, D’Abreo D, Murchison C, Quinn JF, et al. Association of perivascular localization of aquaporin-4 with cognition and Alzheimer disease in aging brains. JAMA Neurol. 2017;74:91–9.

    PubMed  Google Scholar 

  128. Gate D, Saligrama N, Leventhal O, Yang AC, Unger MS, Middeldorp J, et al. Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease. Nature. 2020;577:399–404.

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Pan WR, Suami H, Taylor GI. Lymphatic drainage of the superficial tissues of the head and neck: anatomical study and clinical implications. Plast Reconstr Surg. 2008;121:1614–24.

    CAS  PubMed  Google Scholar 

  130. Tilney NL. Patterns of lymphatic drainage in the adult laboratory rat. J Anat. 1971;109:369–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Sakka L, Coll G, Chazal J. Anatomy and physiology of cerebrospinal fluid. Eur Ann Otorhinolaryngol Head Neck Dis. 2011;128:309–16.

    CAS  PubMed  Google Scholar 

  132. Herisson F, Frodermann V, Courties G, Rohde D, Sun Y, Vandoorne K, et al. Direct vascular channels connect skull bone marrow and the brain surface enabling myeloid cell migration. Nat Neurosci. 2018;21:1209–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Paasonen J, Stenroos P, Salo RA, Kiviniemi V, Gröhn O. Functional connectivity under six anesthesia protocols and the awake condition in rat brain. Neuroimage. 2018;172:9–20.

    PubMed  Google Scholar 

  134. Ringstad G, Vatnehol SAS, Eide PK. Glymphatic MRI in idiopathic normal pressure hydrocephalus. Brain. 2017;140:2691–705.

    PubMed  PubMed Central  Google Scholar 

Download references

Funding

This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Government (MSIP) (No. 2015M3C7A1028926 and No. 2017M3C7A1048079) and NRF grant funded by the Korean Government (No. 2016R1D1A1A02937497 and No. 2017R1A5A1015626).

Author information

Authors and Affiliations

  1. Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea

    Dong Soo Lee, Minseok Suh & Yoori Choi

  2. Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, and College of Medicine or College of Pharmacy, Seoul National University, Seoul, 03080, Republic of Korea

    Dong Soo Lee, Minseok Suh, Azmal Sarker & Yoori Choi

Authors
  1. Dong Soo Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Minseok Suh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Azmal Sarker
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yoori Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dong Soo Lee.

Ethics declarations

Conflict of Interest

Dong Soo Lee, Minseok Suh, Azmal Sarker, and Yoori Choi declare that they have no conflict of interest.

Ethical Approval

All procedures performed in studies were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed Consent

As a review article, obtaining informed consent was waived.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lee, D.S., Suh, M., Sarker, A. et al. Brain Glymphatic/Lymphatic Imaging by MRI and PET. Nucl Med Mol Imaging 54, 207–223 (2020). https://doi.org/10.1007/s13139-020-00665-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13139-020-00665-4

Keywords

Search

Navigation