Skip to main content

Advertisement

SpringerLink
Log in

Evaluation of glymphatic-meningeal lymphatic system with intravenous gadolinium-based contrast-enhancement in cerebral small-vessel disease

  • Neuro
  • Published:
European Radiology Aims and scope Submit manuscript

A Commentary to this article was published on 06 July 2023

Abstract

Objective

To investigate the feasibility of using noninvasive neuroimaging methods in visualizing and evaluating the clearance of the glymphatic-meningeal lymphatic system (GMLS) in patients with arteriosclerotic cerebral small-vessel disease (CSVD) and controls.

Methods

This observational study recruited patients with high-burden CSVD and controls (age 50–80 years). At multiple time points before and after intravenous administration of a contrast agent, three-dimensional (3D) brain volume T1-weighted imaging and 3D Cube T2-fluid attenuated inversion recovery imaging were performed to visualize and assess the clearance of the glymphatics and meningeal lymphatic vessels (mLVs). We measured the signal intensity ratio (SIR) of four regions of interest representing the glymphatics and mLVs at each time point. The clearance rate at 24 h (CR24h) and changes in the SIR from baseline to 24 h (∆SIR) were defined as the clearance function. The analysis of variance was used to evaluate the group differences after adjusting for hypertension.

Results

A total of 20 CSVD patients and 15 controls were included. Cortical periarterial enhancement and the enhancement of enlarged perivascular spaces in the basal ganglia were respectively observed in 11 (55.00%) and 16 (80.00%) CSVD patients, but in none of controls. All CSVD patients and most of controls (80.00%) showed cortical perivenous enhancement. Para-sinus enhancement was observed in all participants. CSVD patients showed lower CR24h and higher ∆SIR of the glymphatics and mLVs (all p < 0.05).

Conclusion

The impaired drainage of the GMLS in patients with high-burden CSVD could be visually evaluated using noninvasive neuroimaging methods with intravenous gadolinium-based contrast-enhancement.

Clinical relevance statement

Dynamic intravenous contrast-enhanced MRI could visually evaluate the impaired drainage of the glymphatic-meningeal lymphatic system in patients with high-burden cerebral small-vessel disease and could help to explore a new therapeutic target.

Key Points

• Signal intensity changes in regions representing the glymphatic-meningeal lymphatic system (GMLS) can reflect the drainage function based on contrast-enhanced 3D-FLAIR and 3D T1-weighted MRI.

• Impaired drainage of the GMLS in patients with high-burden CSVD can be visually evaluated using dynamic intravenous contrast-enhanced MRI.

• This direct, noninvasive technique could serve as a basis for further GMLS studies and could help to explore a new therapeutic target in CSVD patients.

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

Similar content being viewed by others

Abbreviations

3D:

Three-dimensional

BBB:

Blood–brain barrier

BG:

Basal ganglia

BRAVO T1WI:

Brain volume T1-weighted imaging

CSF:

Cerebrospinal fluid

CSVD:

Cerebral small-vessel diseases

DTI-ALPS:

Diffusion tensor image analysis along the perivascular spaces

EPVSs:

Enlarged perivascular spaces

GBCA:

Gadolinium-based contrast agent

GMLS:

Glymphatic-meningeal lymphatic system

mLVs:

Meningeal lymphatic vessels

MMSE:

Mini-Mental State Examination

MoCA:

Montreal Cognitive Assessment

PSQI:

Pittsburgh Sleep Quality Index

RCVS:

Reversible cerebral vasoconstriction syndrome

ROI:

Region of interest

SI:

Signal intensity

SIR:

Signal intensity ratio

SS:

Sigmoid sinus

SSS:

Superior sagittal sinus

T2-FLAIR:

T2-fluid attenuated inversion recovery imaging

TI:

Inversion time

TTP:

Time to peak enhancement

References

  1. Rasmussen MK, Mestre H, Nedergaard M (2018) The glymphatic pathway in neurological disorders. Lancet Neurol 17:1016–1024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Mestre H, Kostrikov S, Mehta RI, Nedergaard M (2017) Perivascular spaces, glymphatic dysfunction, and small vessel disease. Clin Sci (Lond) 131:2257–2274

    Article  CAS  PubMed  Google Scholar 

  3. Wardlaw JM, Benveniste H, Nedergaard M et al (2020) Perivascular spaces in the brain: anatomy, physiology and pathology. Nat Rev Neurol 16:137–153

    Article  PubMed  Google Scholar 

  4. Ahn JH, Cho H, Kim JH et al (2019) Meningeal lymphatic vessels at the skull base drain cerebrospinal fluid. Nature 572:62–66

    Article  CAS  PubMed  Google Scholar 

  5. Louveau A, Smirnov I, Keyes TJ et al (2015) Structural and functional features of central nervous system lymphatic vessels. Nature 523:337–341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Nedergaard M, Goldman SA (2020) Glymphatic failure as a final common pathway to dementia. Science 370:50–56

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Gorelick PB, Scuteri A, Black SE et al (2011) Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the american heart association/american stroke association. Stroke 42:2672–2713

    Article  PubMed  PubMed Central  Google Scholar 

  8. Wardlaw JM, Smith EE, Biessels GJ et al (2013) Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol 12:822–838

    Article  PubMed  PubMed Central  Google Scholar 

  9. Pantoni L (2010) Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol 9:689–701

    Article  PubMed  Google Scholar 

  10. Xue Y, Liu N, Zhang M, Ren X, Tang J, Fu J (2020) Concomitant enlargement of perivascular spaces and decrease in glymphatic transport in an animal model of cerebral small vessel disease. Brain Res Bull 161:78–83

    Article  CAS  PubMed  Google Scholar 

  11. Zhou Y, Cai J, Zhang W et al (2020) Impairment of the glymphatic pathway and putative meningeal lymphatic vessels in the aging human. Ann Neurol 87:357–369

    Article  CAS  PubMed  Google Scholar 

  12. Ding XB, Wang XX, Xia DH et al (2021) Impaired meningeal lymphatic drainage in patients with idiopathic Parkinson’s disease. Nat Med 27:411–418

    Article  CAS  PubMed  Google Scholar 

  13. Mortensen KN, Sanggaard S, Mestre H et al (2019) Impaired glymphatic transport in spontaneously hypertensive rats. J Neurosci 39:6365–6377

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  15. Zhang W, Zhou Y, Wang J et al (2021) Glymphatic clearance function in patients with cerebral small vessel disease. Neuroimage 238:118257

    Article  PubMed  Google Scholar 

  16. Tang J, Zhang M, Liu N et al (2022) The association between glymphatic system dysfunction and cognitive impairment in cerebral small vessel disease. Front Aging Neurosci 14:916633

    Article  PubMed  PubMed Central  Google Scholar 

  17. Wu CH, Lirng JF, Ling YH et al (2021) Noninvasive characterization of human glymphatics and meningeal lymphatics in an in vivo model of blood-brain barrier leakage. Ann Neurol 89:111–124

    Article  CAS  PubMed  Google Scholar 

  18. Naganawa S, Nakane T, Kawai H, Taoka T (2017) Gd-based contrast enhancement of the perivascular spaces in the basal ganglia. Magn Reson Med Sci 16:61–65

    Article  CAS  PubMed  Google Scholar 

  19. Absinta M, Ha SK, Nair G, et al (2017) Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI. Elife.6

  20. Lee MK, Cho SJ, Bae YJ, Kim JM (2022) MRI-based demonstration of the normal glymphatic system in a human population: a systematic review. Front Neurol 13:827398

    Article  PubMed  PubMed Central  Google Scholar 

  21. Lee S, Yoo RE, Choi SH et al (2021) Contrast-enhanced MRI T1 mapping for quantitative evaluation of putative dynamic glymphatic activity in the human brain in sleep-wake states. Radiology 300:661–668

    Article  PubMed  Google Scholar 

  22. Mijnders LS, Steup FW, Lindhout M, van der Kleij PA, Brink WM, van der Molen AJ (2021) Optimal sequences and sequence parameters for GBCA-enhanced MRI of the glymphatic system: a systematic literature review. Acta Radiol 62:1324–1332

    Article  PubMed  Google Scholar 

  23. Naganawa S, Taoka T (2022) The glymphatic system: a review of the challenges in visualizing its structure and function with MR imaging. Magn Reson Med Sci 21:182–194

    Article  CAS  PubMed  Google Scholar 

  24. Albayram MS, Smith G, Tufan F et al (2022) Non-invasive MR imaging of human brain lymphatic networks with connections to cervical lymph nodes. Nat Commun 13:203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Deng W, Lin X, Su Y, Cai Y, Zhong J, Ou Y (2022) Comparison between 3D-FLAIR and 3D-real IR MRI sequences with visual classification method in the imaging of endolymphatic hydrops in Meniere’s disease. Am J Otolaryngol 43:103557

    Article  PubMed  Google Scholar 

  26. Li Y, Li M, Zuo L et al (2018) Compromised blood-brain barrier integrity is associated with total magnetic resonance imaging burden of cerebral small vessel disease. Front Neurol 9:221

    Article  PubMed  PubMed Central  Google Scholar 

  27. Xiao YD, Paudel R, Liu J, Ma C, Zhang ZS, Zhou SK (2016) MRI contrast agents: classification and application (Review). Int J Mol Med 38:1319–1326

    Article  CAS  PubMed  Google Scholar 

  28. Zhang CE, Wong SM, van de Haar HJ et al (2017) Blood-brain barrier leakage is more widespread in patients with cerebral small vessel disease. Neurology 88:426–432

    Article  CAS  PubMed  Google Scholar 

  29. Yang L, Kress BT, Weber HJ et al (2013) Evaluating glymphatic pathway function utilizing clinically relevant intrathecal infusion of CSF tracer. J Transl Med 11:107

    Article  PubMed  PubMed Central  Google Scholar 

  30. Naganawa S, Nakane T, Kawai H, Taoka T (2019) Age dependence of gadolinium leakage from the cortical veins into the cerebrospinal fluid assessed with whole brain 3D-real inversion recovery mr imaging. Magn Reson Med Sci 18:163–169

    Article  CAS  PubMed  Google Scholar 

  31. Naganawa S, Ito R, Kawai H, Taoka T, Yoshida T, Sone M (2020) Confirmation of age-dependence in the leakage of contrast medium around the cortical veins into cerebrospinal fluid after intravenous administration of gadolinium-based contrast agent. Magn Reson Med Sci 19:375–381

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Freeze WM, Schnerr RS, Palm WM et al (2017) Pericortical enhancement on delayed postgadolinium fluid-attenuated inversion recovery images in normal aging, mild cognitive impairment, and Alzheimer disease. AJNR Am J Neuroradiol 38:1742–1747

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  34. Olate-Briones A, Escalona E, Salazar C et al (2022) The meningeal lymphatic vasculature in neuroinflammation. FASEB J 36:e22276

    Article  CAS  PubMed  Google Scholar 

  35. Da Mesquita S, Louveau A, Vaccari A et al (2018) Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease. Nature 560:185–191

    Article  PubMed  PubMed Central  Google Scholar 

  36. Liu N, Xue Y, Tang J, Zhang M, Ren X, Fu J (2021) The dynamic change of phenotypic markers of smooth muscle cells in an animal model of cerebral small vessel disease. Microvasc Res 133:104061

    Article  CAS  PubMed  Google Scholar 

  37. Forsberg KME, Zhang Y, Reiners J et al (2018) Endothelial damage, vascular bagging and remodeling of the microvascular bed in human microangiopathy with deep white matter lesions. Acta Neuropathol Commun 6:128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Prof. Ding Ding for her help with the statistical analyses in this manuscript.

Funding

This study has received funding by the National Natural Science Foundation of China (81901179).

Author information

Author notes

  1. Weijun Tang and Jianhui Fu contributed equally to the work.

Authors and Affiliations

  1. Department of Neurology, Huashan Hospital, Fudan University, No.12 Wulumuqi Zhong Road, Shanghai, 200040, China

    Miaoyi Zhang, Jie Tang, Yang Xue, Xue Ren, Qi Huang, Langfeng Shi & Jianhui Fu

  2. Department of Radiology, Huashan Hospital, Fudan University, No.12 Wulumuqi Zhong Road, Shanghai, 200040, China

    Ding Xia & Weijun Tang

Authors
  1. Miaoyi Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jie Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ding Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yang Xue
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xue Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Qi Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Langfeng Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Weijun Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jianhui Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Weijun Tang or Jianhui Fu.

Ethics declarations

Guarantor

The scientific guarantor of this publication is Jianhui Fu.

Conflict of interest

The authors of this manuscript declare no relationships with any companies whose products or services may be related to the subject matter of the article.

Statistics and biometry

Prof. Ding Ding kindly provided statistical advice for this manuscript.

Informed consent

Written informed consent was obtained from all subjects (patients) in this study.

Ethical approval

Institutional Review Board approval was obtained.

Study subjects or cohorts overlap

The enrolled patients with arteriosclerotic CSVD in the current study were recruited from our registered prospective cohort (registration number: ChiCTR1800017902). The inclusion and exclusion criteria of this cohort have been reported previously (Front Aging Neurosci 2022;14:916633). The methodology in the current study has not been published before.

Methodology

• observational

• performed at one institution

Additional information

Publisher's note

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

Miaoyi Zhang and Jie Tang are co-first authors.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 255 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, M., Tang, J., Xia, D. et al. Evaluation of glymphatic-meningeal lymphatic system with intravenous gadolinium-based contrast-enhancement in cerebral small-vessel disease. Eur Radiol 33, 6096–6106 (2023). https://doi.org/10.1007/s00330-023-09796-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00330-023-09796-6

Keywords

Search

Navigation