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Reperfusion facilitates reversible disruption of the human blood–brain barrier following acute ischaemic stroke

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Abstract

Objectives

We aimed to detect early changes of the blood–brain barrier permeability (BBBP) in acute ischaemic stroke (AIS), with or without reperfusion, and find out whether BBBP can predict clinical outcomes.

Methods

Consecutive AIS patients imaged with computed tomographic perfusion (CTP) before and 24 h after treatment were included. The relative permeability–surface area product (rPS) was calculated within the hypoperfused region (rPShypo-i), non-hypoperfused region of ischaemic hemisphere (rPSnonhypo-i) and their contralateral mirror regions (rPShypo-c and rPSnonhypo-c). The changes of rPS were analysed using analysis of variance (ANOVA) with repeated measures. Logistic regression was used to identify independent predictors of unfavourable outcome.

Results

Fifty-six patients were included in the analysis, median age was 76 (IQR 62–81) years and 28 (50%) were female. From baseline to 24 h after treatment, rPShypo-i, rPSnonhypo-i and rPShypo-c all decreased significantly. The decreases in rPShypo-i and rPShypo-c were larger in the reperfusion group than non-reperfusion group. The rPShypo-i at follow-up was a predictor for unfavourable outcome (OR 1.131; 95% CI 1.018–1.256; P = 0.022).

Conclusion

Early disruption of BBB in AIS is reversible, particularly when greater reperfusion is achieved. Elevated BBBP at 24 h after treatment, not the pretreatment BBBP, predicts unfavourable outcome.

Key points

• Early disruption of blood–brain barrier (BBB) in stroke is reversible after treatment.

• The reversibility of BBB permeability is associated with reperfusion.

• Unfavourable outcome is associated with BBB permeability at 24 h after treatment.

• Contralateral non-ischaemic hemisphere is not ‘normal’ during an acute stroke.

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Abbreviations

AATH:

adiabatic approximation of tissue homogeneity

AIS:

acute ischaemic stroke

ANOVA:

analysis of variance

BBB:

blood–brain barrier

BBBP:

BBB permeability

CBF:

cerebral blood flow

CBV:

cerebral blood volume

CI:

confidence interval

CTP:

computed tomographic perfusion

ECs:

endothelial cells

HT:

haemorrhagic transformation

IQR:

interquartile range

IVT:

intravenous thrombolysis

mRS:

modified Rankin Scale

NIHSS:

National Institutes of Health Stroke Scale

ONT:

onset-to-needle time

OR:

odds ratio

PS:

permeability–surface area product

rCBF:

relative CBF

ROI:

regions of interest

rPS:

relative PS

rPShypo-c :

rPS of contralateral mirror hypoperfusion region

rPShypo-i :

rPS of ipsilateral hypoperfusion region

rPSnonhypo-c :

rPS of contralateral mirror non-hypoperfusion region

rPSnonhypo-i :

rPS of ipsilateral non-hypoperfusion region

RR:

reperfusion rate

TJPs:

tight junction proteins

tPA:

tissue-type plasminogen activator

VPCT:

volume perfusion CT

References

  1. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group (1995) Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 333:1581–1587

    Article  Google Scholar 

  2. Niego B, Medcalf RL (2014) Plasmin-dependent modulation of the blood–brain barrier: a major consideration during tPA-induced thrombolysis? J Cereb Blood Flow Metab 34:1283–1296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Hom J, Dankbaar JW, Soares BP et al (2011) Blood–brain barrier permeability assessed by perfusion CT predicts symptomatic hemorrhagic transformation and malignant edema in acute ischemic stroke. AJNR Am J Neuroradiol 32:41–48

    Article  CAS  PubMed  Google Scholar 

  4. Dankbaar JW, Hom J, Schneider T et al (2009) Age- and anatomy-related values of blood–brain barrier permeability measured by perfusion-CT in non-stroke patients. J Neuroradiol 36:219–227

    Article  CAS  PubMed  Google Scholar 

  5. Dankbaar JW, Hom J, Schneider T et al (2008) Dynamic perfusion CT assessment of the blood–brain barrier permeability: first pass versus delayed acquisition. AJNR Am J Neuroradiol 29:1671–1676

    Article  CAS  PubMed  Google Scholar 

  6. Aviv RI, d'Esterre CD, Murphy BD et al (2009) Hemorrhagic transformation of ischemic stroke: prediction with CT perfusion. Radiology 250:867–877

    Article  PubMed  Google Scholar 

  7. Shi Y, Leak RK, Keep RF, Chen J (2016) Translational stroke research on blood–brain barrier damage: challenges, perspectives, and goals. Transl Stroke Res 7:89–92

    Article  PubMed  PubMed Central  Google Scholar 

  8. Simpkins AN, Dias C, Leigh R, National Institutes of Health Natural History of Stroke Investigators (2016) Identification of reversible disruption of the human blood–brain barrier following acute ischemia. Stroke 47:2405–2408

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Garbuzova-Davis S, Haller E, Williams SN et al (2014) Compromised blood–brain barrier competence in remote brain areas in ischemic stroke rats at the chronic stage. J Comp Neurol 522:3120–3137

    Article  PubMed  PubMed Central  Google Scholar 

  10. Garbuzova-Davis S, Rodrigues MC, Hernandez-Ontiveros DG et al (2013) Blood–brain barrier alterations provide evidence of subacute diaschisis in an ischemic stroke rat model. PLoS One 8:e63553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Haberg AK, Qu H, Sonnewald U (2009) Acute changes in intermediary metabolism in cerebellum and contralateral hemisphere following middle cerebral artery occlusion in rat. J Neurochem 109:174–181

    Article  PubMed  Google Scholar 

  12. Lorberboym M, Blankenberg FG, Sadeh M, Lampl Y (2006) In vivo imaging of apoptosis in patients with acute stroke: correlation with blood–brain barrier permeability. Brain Res 1103:13–19

    Article  CAS  PubMed  Google Scholar 

  13. Mari C, Karabiyikoglu M, Goris ML, Tait JF, Yenari MA, Blankenberg FG (2004) Detection of focal hypoxic-ischemic injury and neuronal stress in a rodent model of unilateral MCA occlusion/reperfusion using radiolabeled annexin V. Eur J Nucl Med Mol Imaging 31:733–739

    Article  CAS  PubMed  Google Scholar 

  14. Jauch EC, Saver JL, Adams HP Jr et al (2013) Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 44:870–947

    Article  PubMed  Google Scholar 

  15. Horsch AD, Dankbaar JW, van Seeters T et al (2016) Relation between stroke severity, patient characteristics and CT-perfusion derived blood–brain barrier permeability measurements in acute ischemic stroke. Clin Neuroradiol 26:415–421

    Article  PubMed  Google Scholar 

  16. St Lawrence KS, Lee TY (1998) An adiabatic approximation to the tissue homogeneity model for water exchange in the brain: I. Theoretical derivation. J Cereb Blood Flow Metab 18:1365–1377

    Article  CAS  PubMed  Google Scholar 

  17. Lin L, Bivard A, Levi CR, Parsons MW (2014) Comparison of computed tomographic and magnetic resonance perfusion measurements in acute ischemic stroke: back-to-back quantitative analysis. Stroke 45:1727–1732

    Article  PubMed  Google Scholar 

  18. Eilaghi A, Brooks J, d'Esterre C et al (2013) Reperfusion is a stronger predictor of good clinical outcome than recanalization in ischemic stroke. Radiology 269:240–248

    Article  PubMed  Google Scholar 

  19. Yu Y, Han Q, Ding X et al (2016) Defining core and penumbra in ischemic stroke: a voxel- and volume-based analysis of whole brain CT perfusion. Sci Rep 6:20932

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Zhang S, Tang H, Yu YN, Yan SQ, Parsons MW, Lou M (2015) Optimal magnetic resonance perfusion thresholds identifying ischemic penumbra and infarct core: a Chinese population-based study. CNS Neurosci Ther 21:289–295

    Article  PubMed  Google Scholar 

  21. Zhang X, Zhang S, Chen Q, Ding W, Campbell BCV, Lou M (2017) Ipsilateral prominent thalamostriate vein on susceptibility-weighted imaging predicts poor outcome after intravenous thrombolysis in acute ischemic stroke. AJNR Am J Neuroradiol 38:875–881

    Article  CAS  PubMed  Google Scholar 

  22. Zhou Y, Zhang R, Zhang S et al (2017) Impact of perfusion lesion in corticospinal tract on response to reperfusion. Eur Radiol. doi:10.1007/s00330-017-4868-y

  23. Knowland D, Arac A, Sekiguchi KJ et al (2014) Stepwise recruitment of transcellular and paracellular pathways underlies blood–brain barrier breakdown in stroke. Neuron 82:603–617

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Shi Y, Zhang L, Pu H et al (2016) Rapid endothelial cytoskeletal reorganization enables early blood–brain barrier disruption and long-term ischaemic reperfusion brain injury. Nature Communications 7:10523

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Yang Y, Estrada EY, Thompson JF, Liu W, Rosenberg GA (2007) Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat. J Cereb Blood Flow Metab 27:697–709

    Article  CAS  PubMed  Google Scholar 

  26. Jin X, Liu J, Yang Y, Liu KJ, Yang Y, Liu W (2012) Spatiotemporal evolution of blood brain barrier damage and tissue infarction within the first 3h after ischemia onset. Neurobiol Dis 48:309–316

    Article  PubMed  Google Scholar 

  27. Sandoval KE, Witt KA (2008) Blood–brain barrier tight junction permeability and ischemic stroke. Neurobiol Dis 32:200–219

    Article  CAS  PubMed  Google Scholar 

  28. Carrera E, Tononi G (2014) Diaschisis: past, present, future. Brain 137:2408–2422

    Article  PubMed  Google Scholar 

  29. Lagreze HL, Levine RL, Pedula KL, Nickles RJ, Sunderland JS, Rowe BR (1987) Contralateral flow reduction in unilateral stroke: evidence for transhemispheric diaschisis. Stroke 18:882–886

    Article  CAS  PubMed  Google Scholar 

  30. Meyer JS, Obara K, Muramatsu K (1993) Diaschisis. Neurol Res 15:362–366

    Article  CAS  PubMed  Google Scholar 

  31. Arango-Davila CA, Munoz Ospina BE, Castano DM, Potes L, Umbarila Prieto J (2016) Assessment transcallosal diaschisis in a model of focal cerebral ischemia in rats. Colomb Med (Cali) 47:87–93

    Google Scholar 

  32. Nguyen GT, Coulthard A, Wong A et al (2013) Measurement of blood–brain barrier permeability in acute ischemic stroke using standard first-pass perfusion CT data. Neuroimage Clin 2:658–662

    Article  PubMed  PubMed Central  Google Scholar 

  33. Hom J, Dankbaar JW, Schneider T, Cheng SC, Bredno J, Wintermark M (2009) Optimal duration of acquisition for dynamic perfusion CT assessment of blood–brain barrier permeability using the Patlak model. AJNR Am J Neuroradiol 30:1366–1370

    Article  CAS  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Neurology, The Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, China

    Chang Liu, Sheng Zhang, Shenqiang Yan, Ruiting Zhang, Feina Shi & Min Lou

  2. Department of Radiology, The Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, China

    Xinfa Ding

  3. Department of Neurology, John Hunter Hospital, University of Newcastle, Newcastle, Australia

    Mark Parsons

Authors
  1. Chang Liu
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  2. Sheng Zhang
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  3. Shenqiang Yan
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  4. Ruiting Zhang
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  7. Mark Parsons
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  8. Min Lou
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Corresponding author

Correspondence to Min Lou.

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Guarantor

The scientific guarantor of this publication is Min Lou.

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.

Funding

This work was supported by the National Natural Science Foundation of China (81471170 & 81622017 & 81601017) and the National Key Research and Development Program of China (2016 YFC 1301500). The perfusion analysis software (MIStar) was provided to the site as part of their involvement in the International Stroke Perfusion Imaging Registry (INSPIRE, www.Inspire.apollomit.com/), study funded by the National Health and Medical Research Council of Australia.

Statistics and biometry

No complex statistical methods were necessary for this paper.

Informed consent

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

Ethical approval

Institutional review board approval was obtained.

Methodology

• retrospective

• observational

• performed at one institution

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Liu, C., Zhang, S., Yan, S. et al. Reperfusion facilitates reversible disruption of the human blood–brain barrier following acute ischaemic stroke. Eur Radiol 28, 642–649 (2018). https://doi.org/10.1007/s00330-017-5025-3

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  • DOI: https://doi.org/10.1007/s00330-017-5025-3

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