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A contrast agent recognizing activated platelets reveals murine cerebral malaria pathology undetectable by conventional MRI
Constantin von zur Muhlen, … , Robin P. Choudhury, Daniel C. Anthony
Constantin von zur Muhlen, … , Robin P. Choudhury, Daniel C. Anthony
Published February 14, 2008
Citation Information: J Clin Invest. 2008;118(3):1198-1207. https://doi.org/10.1172/JCI33314.
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Technical Advance Neuroscience

A contrast agent recognizing activated platelets reveals murine cerebral malaria pathology undetectable by conventional MRI

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Abstract

Human and murine cerebral malaria are associated with elevated levels of cytokines in the brain and adherence of platelets to the microvasculature. Here we demonstrated that the accumulation of platelets in the brain microvasculature can be detected with MRI, using what we believe to be a novel contrast agent, at a time when the pathology is undetectable by conventional MRI. Ligand-induced binding sites (LIBS) on activated platelet glycoprotein IIb/IIIa receptors were detected in the brains of malaria-infected mice 6 days after inoculation with Plasmodium berghei using microparticles of iron oxide (MPIOs) conjugated to a single-chain antibody specific for the LIBS (LIBS-MPIO). No binding of the LIBS-MPIO contrast agent was detected in uninfected animals. A combination of LIBS-MPIO MRI, confocal microscopy, and transmission electron microscopy revealed that the proinflammatory cytokine TNF-α, but not IL-1β or lymphotoxin-α (LT-α), induced adherence of platelets to cerebrovascular endothelium. Peak platelet adhesion was found 12 h after TNF-α injection and was readily detected with LIBS-MPIO contrast-enhanced MRI. Temporal studies revealed that the level of MPIO-induced contrast was proportional to the number of platelets bound. Thus, the LIBS-MPIO contrast agent enabled noninvasive detection of otherwise undetectable cerebral pathology by in vivo MRI before the appearance of clinical disease, highlighting the potential of targeted contrast agents for diagnostic, mechanistic, and therapeutic studies.

Authors

Constantin von zur Muhlen, Nicola R. Sibson, Karlheinz Peter, Sandra J. Campbell, Panop Wilainam, Georges E. Grau, Christoph Bode, Robin P. Choudhury, Daniel C. Anthony

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Figure 1

Conventional imaging of murine CM.

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Conventional imaging of murine CM.
(A) Coronal T1-weighted image acquire...
(A) Coronal T1-weighted image acquired 7 days after the injection of 106P. berghei ANKA–parasitized rbcs. (B) T1-weighted image from the same animal following injection of Gd-DTPA. Note the regions of increased signal intensity compared with A, indicating blood-brain barrier breakdown (arrow). (C) T2-weighted image of the same slice showing increased signal intensity in the same regions as the Gd-DTPA enhancement. (D) Significant elevation in T2 in the hippocampi of day-7 terminal-stage CM mice (P < 0.05).

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