PET-MRI nanoparticles imaging of blood–brain barrier damage and modulation after stroke reperfusion

• Published in: Brain communications Vol. 2; no. 2; p. fcaa193
• Main Authors: Debatisse, Justine, Eker, Omer Faruk, Wateau, Océane, Cho, Tae-Hee, Wiart, Marlène, Ramonet, David, Costes, Nicolas, Mérida, Inés, Léon, Christelle, Dia, Maya, Paillard, Mélanie, Confais, Joachim, Rossetti, Fabien, Langlois, Jean-Baptiste, Troalen, Thomas, Iecker, Thibaut, Le Bars, Didier, Lancelot, Sophie, Bouchier, Baptiste, Lukasziewicz, Anne-Claire, Oudotte, Adrien, Nighoghossian, Norbert, Ovize, Michel, Contamin, Hugues, Lux, François, Tillement, Olivier, Canet-Soulas, Emmanuelle
• Format: Journal Article
• Language: English
• Published: Oxford University Press 01.01.2020; Oxford University Press on behalf of the Guarantors of Brain
• Subjects: Bioengineering; Life Sciences; Original; ischaemia–reperfusion damage; nanoparticles; blood–brain barrier; stroke; choroid plexus; blood-brain barrier; ischaemia-reperfusion damage
• ISSN: 2632-1297; 2632-1297
• DOI: 10.1093/braincomms/fcaa193

Abstract In an acute ischaemic stroke, understanding the dynamics of blood–brain barrier injury is of particular importance for the prevention of symptomatic haemorrhagic transformation. However, the available techniques assessing blood–brain barrier permeability are not quantitative and are little used in the context of acute reperfusion therapy. Nanoparticles cross the healthy or impaired blood–brain barrier through combined passive and active processes. Imaging and quantifying their transfer rate could better characterize blood–brain barrier damage and refine the delivery of neuroprotective agents. We previously developed an original endovascular stroke model of acute ischaemic stroke treated by mechanical thrombectomy followed by positron emission tomography-magnetic resonance imaging. Cerebral capillary permeability was quantified for two molecule sizes: small clinical gadolinium Gd-DOTA (<1 nm) and AGuIX® nanoparticles (∼5 nm) used for brain theranostics. On dynamic contrast-enhanced magnetic resonance imaging, the baseline transfer constant Ktrans was 0.94 [0.48, 1.72] and 0.16 [0.08, 0.33] ×10−3 min−1, respectively, in the normal brain parenchyma, consistent with their respective sizes, and 1.90 [1.23, 3.95] and 2.86 [1.39, 4.52] ×10−3 min−1 in choroid plexus, confirming higher permeability than brain parenchyma. At early reperfusion, Ktrans for both Gd-DOTA and AGuIX® nanoparticles was significantly higher within the ischaemic area compared to the contralateral hemisphere; 2.23 [1.17, 4.13] and 0.82 [0.46, 1.87] ×10−3 min−1 for Gd-DOTA and AGuIX® nanoparticles, respectively. With AGuIX® nanoparticles, Ktrans also increased within the ischaemic growth areas, suggesting added value for AGuIX®. Finally, Ktrans was significantly lower in both the lesion and the choroid plexus in a drug-treated group (ciclosporin A, n = 7) compared to placebo (n = 5). Ktrans quantification with AGuIX® nanoparticles can monitor early blood–brain barrier damage and treatment effect in ischaemic stroke after reperfusion. Blood–brain barrier damage is the next target for neuroprotection after stroke ischaemia–reperfusion. Debatisse et al. used PET-MRI nanoparticles imaging for its precise quantification. Both brain infarct and choroid plexus permeabilities were significantly increased 2 h after recanalization. Finally, they were both decreased by a single ciclosporin A injection. Graphical Abstract Graphical Abstract