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Imaging of Glymphatic Flow and Neurodegeneration

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Hybrid PET/MR Neuroimaging

Abstract

Alzheimer’s disease (AD) is the most common form of dementia affecting over four million people in the United States with expected doubling by 2025. It remains a major public health problem that currently affects one out of nine people over the age of 65 and up to one-third of those over 85 [1]. AD patients develop cognitive impairment which progresses until they can no longer perform routine activities of daily living or function independently. Advances in medical treatment that have improved longevity, and the aging baby boomer population will dramatically increase the numbers of elderly AD patients, underscoring an urgent need for improvements in the early diagnosis and therapeutic management of AD.

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References

  1. Borthakur A, Gur T, Wheaton AJ, et al. In vivo measurement of plaque burden in a mouse model of Alzheimer’s disease. J Magn Reson Imaging. 2006;24(5):1011–7.

    PubMed  PubMed Central  Google Scholar 

  2. Selkoe DJ. Translating cell biology into therapeutic advances in Alzheimer’s disease. Nature. 1999;399:A23–31.

    CAS  PubMed  Google Scholar 

  3. Lee VM, Goedert M, Trojanowski JQ. Neurodegenerative tauopathies. Annu Rev Neurosci. 2001;24:1121–59.

    CAS  PubMed  Google Scholar 

  4. Jessen NA, Finnman-Munk AS, Lundgaard I, Nedergaard M. The glymphatic system: a beginner’s guide. Neurochem Res. 2015;40:2583–99.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Damkier HH, Brown PD, Praetorius J. Cerebrospinal Fluid Secretion by the Choroid Plexus. Physiol Rev 2013;93(4):1847–92.

    Google Scholar 

  6. Johansen CE, Duncan JA, Klinge PM, et al. Multiplicity of cerebrospinal fluid functions: new challenges in health and diseases. Cerebrospinal Fluid Res. 2008;5:10.

    Google Scholar 

  7. Thrane AS, Rangroo Thrane V, Nedergaard M. Drowning stars: reassessing the role of astrocytes in brain edema. Trends Neurosci. 2014;37:620–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Brown P, Davies S, Speake T, Miller I. Molecular mechanisms of cerebrospinal fluid production. Neuroscience. 2004;129:957–70.

    CAS  PubMed  Google Scholar 

  9. Zlokovic BV. Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nat Rev Neurosci. 2011;12:273–738.

    Google Scholar 

  10. Zhang ET, Inman CB, Weller RO. Interrelationships of the pia mater and the perivascular (Virchow Robin) spaces in the human cerebrum. J Anat. 1990;170:111–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Kulik T, Kusano Y, Aronhime S. Regulation of cerebral vasculature in normal and ischemic brain. Neuropharmacology. 2008;55:281–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. del Zoppo GJ, Moskowitz M, Nedergaard M. The neurovascular unit and responses to ischemia. In: Grotta J, Albers G, Broderick J, Kasner S, Lo E, Medelow AD, Sacco R, Wong L, editors. Stroke: pathophysiology, diagnosis, and management. 6th ed. Philadelphia: Elsevier; 2015.

    Google Scholar 

  13. Iliff JJ, Wang M, Liao Y, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid B. Sci Transl Med. 2012;4:147.

    Google Scholar 

  14. Iliff JJ, Nedergaard M. Is there a cerebral lymphatic system? Stroke. 2013;44:S93–5.

    PubMed  PubMed Central  Google Scholar 

  15. Johnston M, Zakharov A, Papaiconomou C, et al. Evidence of connections between cerebrospinal fluid and nasal lymphatic vessels in humans, non-human primates, and other mammalian species. Cerebrospinal Fluid Res. 2004;1:2.

    PubMed  PubMed Central  Google Scholar 

  16. Murtha LA, Yang Q, Parsons MW, et al. Cerebrospinal fluid is drained primarily via the spinal canal and olfactory route in young and aged spontaneously hypertensive rats. Fluids Barrier CNS. 2014;11:12.

    Google Scholar 

  17. Bradbury M, Cserr H. Drainage of cerebral interstitial fluid and of cerebrospinal fluid into lymphatics. In: Johnston M, editor. Experimental biology of the lymphatic circulation. New York: Elsevier; 1985. p. 355–94.

    Google Scholar 

  18. Weller RO, Subash M, Preston SD, et al. Perivascular drainage of amyloid-beta peptides from the brain and its failure in cerebral amyloid angiopathy and Alzheimer’s disease. Brain Pathol. 2008;18:253–66.

    CAS  PubMed  Google Scholar 

  19. Hawkes CA, Sullivan PM, Hands S, et al. Disruption of arterial perivascular drainage of amyloid-beta from the brains of mice expressing the human APOE epsilon4 allele. PLoS One. 2012;7(7):e41636.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Iliff JJ, Chen MJ, Plog BA, et al. Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury. J Neurosci. 2014;34(49):16180–93.

    PubMed  PubMed Central  Google Scholar 

  21. Carare RO, Bernardes-Silva M, Newman TA, et al. Solutes, but not cells, drain from the brain parenchyma along basement membranes of capillaries and arteries: significance for cerebral amyloid angiopathy and neuroimmunology. Neuropathol Appl Neurobiol. 2008;34:131–44.

    CAS  PubMed  Google Scholar 

  22. Hawkes CA, Hartig W, Kacza J, et al. Perivascular drainage of solutes is impaired in the aging mouse brain and in the presence of cerebral amyloid angiopathy. Acta Neuropathol. 2011;121:431–43.

    PubMed  Google Scholar 

  23. Holter KE, Kelhet B, Devor A, et al. Interstitial solute transport in 3D reconstructed neuropil occurs by diffusion rather than bulk flow. PNAS. 2017;114(37):9894–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Ray L, Iliff JJ, Heys JJ. Analysis of convective and diffusive transport in the brain interstitium. Fluids Barriers CNS. 2019;16(1):6. https://doi.org/10.1186/s12987-019-0126-9.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Xie L, Kang H, Xu Q, et al. Sleep drives metabolite clearance from the adult brain. Science. 2013;342:373–7.

    CAS  PubMed  Google Scholar 

  26. Kress BT, Iliff JJ, Xia M, et al. Impairment of the paravascular clearance pathways in the aging brain. Ann Neurol. 2014;10:1002.

    Google Scholar 

  27. Mander BA, Winer JR, Jagust WJ, Walker MP. Sleep: A Novel Mechanistic Pathway, Biomarker, and Treatment Target in the Pathology of Alzheimer’s Disease? Trends Neurosci 2016;39(8):552–66.

    Google Scholar 

  28. Cedernaes J, Osorio RS, Varga AW et al. Candidate Mechanisms Underlying the Association Between Sleep-Wake Disruptions and Alzheimer’s Disease. Sleep Med Review 2017;31:102–111.

    Google Scholar 

  29. Mander BA, Marks SM, Vogel JM, et al. Beta-amyloid disrupts human NREM slow waves and related hippocampus-dependent memory consolidation. Nat Neurosci. 2015;18(7):1051–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Cedernaes J, Osorio RS, Varga AW, et al. Candidate mechanisms underlying the association between sleep-wake disruptions and Alzheimer’s disease. Sleep Med Rev. 2016; epub ahead of print.

    Google Scholar 

  31. Peng W, Achariyar TM, Li B, et al. Suppression of glymphatic fluid transport in a mouse model of Alzheimer’s disease. Neurobiol Dis. 2016;93:215–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Gaberel T, Gakuba C, Goulay R, Martinez De Lizarrondo S, Hanouz JL, Emery E, Touze E, Vivien D, Gauberti M. Impaired glymphatic perfusion after strokes revealed by contrast-enhanced MRI: a new target for fibrinolysis? Stroke. 2014;45(10):3092–6.

    CAS  PubMed  Google Scholar 

  33. Iliff JJ, Wang M, Zeppenfeld DM, 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 

  34. Sabbatini M, Barili P, Bronzetti E, et al. Age-related changes of glial fibrillary acidic protein immunoreactive astrocytes in the rat cerebellar cortex. Mech Ageing Dev. 1999;108:165–72.

    CAS  PubMed  Google Scholar 

  35. Deane R, Zlokovic BV. Role of the blood-brain barrier in the pathogenesis of Alzheimer’s disease. Curr Alzheimer Res. 2007;4:191–7.

    CAS  PubMed  Google Scholar 

  36. Chen RL, Kassem NA, Redzic ZB, et al. Age-related changes in choroid plexus and blood-cerebrospinal fluid barrier function in the sheep. Exp Gerontol. 2009;44:289–96.

    CAS  PubMed  Google Scholar 

  37. Fleischman D, Berdahl JP, Zaydlarova J, et al. Cerebrospinal fluid pressure decreases with older age. PLoS One. 2012;7:e53644.

    Google Scholar 

  38. Zieman SJ, Melenovsky V, Kass DA, et al. Mechanisms, pathophysiology, and therapy of arterial stiffness. Arterioscler Thromb Vasc Biol. 2005;25:932–43.

    CAS  PubMed  Google Scholar 

  39. Takalo M, Salminen A, Soininen H, et al. Protein aggregation and degradation mechanisms in neurodegenerative disease. Am J Neurodegener Dis. 2013;2:1–14.

    PubMed  PubMed Central  Google Scholar 

  40. Frost B, Jacks RL, Diamond MI. Propagation of tau misfolding from the outside to the inside of a cell. J Biol Chem. 2009;284:12845–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Grad LI, Yerbury JJ, Turner BJ, et al. Intracellular propagated misfolding of wild-type Cu/Zn superoxide dismutase occurs via exosome-dependent and –independent mechanisms. Proc Natl Acad Sci U S A. 2014;111:3620–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Kordower JH, Chu Y, Hauser RA, et al. Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson’s disease. Nat Med. 2008;14:504–6.

    CAS  PubMed  Google Scholar 

  43. LI JY, Englund E, Holton JL, et al. Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation. Nat Med. 2008;14:501–3.

    CAS  PubMed  Google Scholar 

  44. Yamada K, Cirrito JR, Stewart FR, et al. In vivo microdialysis reveals age-dependent decrease of brain interstitial fluid tau levels in P301S human tau transgenic mice. J Neurosci. 2011;31:13110–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Iliff JJ, Lee H, Yu M, Feng T, Logan J, Nedergaard M, Benveniste H. Brain-wide pathway for waste clearance captured by contrast-enhanced MRI. J Clin Invest. 2013;123(3):1299–309.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Jost G, Lenhard DC, Sieber MA, Lohrke J, Fenzel T, Pietsch H. Signal increase on unenhanced T1-weighted images in the rat brain after repeated, extended doses of gadolinium-based contrast agents: comparisons of linear and macrocyclic agents. Investig Radiol. 2016;51:83–9.

    CAS  Google Scholar 

  47. Eide PK, Ringstad G. MRI with intrathecal MRI gadolinium contrast medium administration: a possible method to assess glymphatic function in human brain. Acta Radiol Open. 2015;4(11):2058460115609635.

    PubMed  PubMed Central  Google Scholar 

  48. Eide PK, 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. 2018;39(7):1355–68.

    PubMed  PubMed Central  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  50. Lee H, Xie L, Yu M, Kang H, Feng T, Deane R, Logan J, Nedergaard M, Benveniste H. The effect of body posture on brain glymphatic transport. J Neurosci. 2015;35(31):11034–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Kapoor R, Liu J, Devasenapathy A, Gordin V. Gadolinium encephalopathy after intrathecal gadolinium injection. Pain Physician. 2010;13(5):E321–6.

    PubMed  Google Scholar 

  52. Parissis D, Ioannidis P, Karacostas D. Intrathecal gadolinium for magnetic resonance myelography in spontaneous intracranial hypotension: valuable but may be risky. JAMA Neurol. 2014;71(6):802.

    PubMed  Google Scholar 

  53. Kuo YT, Herlihy AH, So PW, Bhakoo KK, Bell JD. In vivo measurements of T1 relaxation times in mouse brain associated with different modes of systemic administration of manganese chloride. J Magn Reson Imaging. 2005;21(4):334–9.

    PubMed  Google Scholar 

  54. Cheng HL, Wright GA. Rapid high-resolution T1 mapping by variable flip angles: accurate and precise measurements in the presence of radiofrequency field inhomogeneity. Magn Reson Med. 2006;55(3):566–74.

    PubMed  Google Scholar 

  55. Watts R, Steinklein JM, Waldman L, Zhou X, Filippi CG. Measuring glymphatic flow in man using contrast-enhanced MRI. AJNR Am J Neuroradiol. 2019;40(4):648–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Dyke JP, Xu HS, Verma A, Voss HU, Chazen JL. MRI characterization of early CNS transport kinetics post intrathecal gadolinium injection: trends of subarachnoid and parenchymal distribution in healthy volunteers. Clin Imaging. 2020;68:1–6.

    PubMed  Google Scholar 

  57. Edeklev CS, Halvorsen M, Lobland G, et al. Intrathecal use of gadobutrol for glymphatic imaging: prospective safety study of 100 patients. AJNR Am J Neuroradiol. 2019;40(8):1257–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Cao Y, Huang DQ, Shih G, Prince MR. Signal changes in the dentate nucleus on T1-weighted MR images after multiple administrations of gadopentetate dimeglumine versus gadobutrol. ANJR Am J Neuroradiol. 2016:414–9.

    Google Scholar 

  59. Lee JY, Park JE, Kim HS, et al. Up to 52 Administrations of Macrocyclic Ionic MR Contrast Agent Are Not Associated with Intracranial Deposition: Multifactorial Analysis in 385 Patients. PLoS One 2017;12(8):e0183916. https://doi.org/10.1371/journal.pone.0183916. eCollection 2017.

  60. Selcuk H, Albayram S, Ozer H, et al. Intrathecal gadolinium-enhanced MR cisternography in the evaluation of CSF leakage. AJNR Am J Neuroradiol. 2010;31(1):71–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Amrhein TJ, Kranz PG. Spontaneous intracranial hypotension: imaging in diagnosis and treatment. Radiol Clin N Am. 2019;57(2):439–51.

    PubMed  Google Scholar 

  62. Eide PK, Valnes LM, Pripp AH, Mardal K, Ringstad G. Delayed clearance of cerebrospinal fluid tracer from choroid plexus in idiopathic normal pressure hydrocephalus. J Cereb Blood Flow Metab. 2019; epub ahead of print.

    Google Scholar 

  63. Wardlaw JM, Benveniste H, Nedergaard M, et al. Perivascular spaces in the brain: anatomy, physiology, and pathology. Nat Rev Neurol. 2020;16:137–53.

    PubMed  Google Scholar 

  64. Albes G, Weng H, Horvath D, Musahl C, Bazner H, Henkes H. Detection and treatment of spinal CSF leaks in idiopathic intracranial hypotension. Neuroradiology. 2012;54(12):1367–73.

    CAS  PubMed  Google Scholar 

  65. Naganawa S, Ito R, Taoka T, Yoshida T, Sone M. The space between the pial sheath and the cortical venous wall may connect to the meningeal lymphatics. Magn Reson Med Sci. 2020;19(1):1–4.

    PubMed  Google Scholar 

  66. Taoka T, Mastuani Y, Kawai H, et al. Evaluation of glymphatic system activity with the diffusion MR technique: Diffusion Tensor Image Analysis Along the Perivascular Space (DTI-ALPS). Jpn J Radiol. 2017;35(4):172–8.

    PubMed  Google Scholar 

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Filippi, C.G., Watts, R. (2022). Imaging of Glymphatic Flow and Neurodegeneration. In: Franceschi, A.M., Franceschi, D. (eds) Hybrid PET/MR Neuroimaging. Springer, Cham. https://doi.org/10.1007/978-3-030-82367-2_71

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  • DOI: https://doi.org/10.1007/978-3-030-82367-2_71

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