Related Experiment Video
Updated: Jul 7, 2026
In Vivo Tracking of Edema Development and Microvascular Pathology in a Model of Experimental Cerebral Malaria Using Magnetic Resonance Imaging
Published on: June 8, 2017
A contrast agent recognizing activated platelets reveals murine cerebral malaria pathology undetectable by
Constantin von Zur Muhlen1, Nicola R Sibson, Karlheinz Peter
1Department of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom.
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-alpha, but not IL-1beta or lymphotoxin-alpha (LT-alpha), induced adherence of platelets to cerebrovascular endothelium. Peak platelet adhesion was found 12 h after TNF-alpha 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.
Insights
Novel MRI contrast agents detect early cerebral malaria pathology by visualizing platelet accumulation in the brain. This allows for noninvasive detection before clinical signs appear, aiding diagnosis and research.
Area of Science:
- Neuroscience
- Immunology
- Biomedical Imaging
Background:
- Cerebral malaria involves brain cytokine elevation and platelet adhesion.
- Current MRI methods cannot detect early-stage cerebral malaria pathology.
Purpose of the Study:
- To develop and validate a novel MRI contrast agent for detecting early cerebral malaria.
- To investigate the role of specific cytokines in platelet adhesion in cerebral malaria.
Main Methods:
- Utilized ligand-induced binding sites (LIBS) on activated platelet glycoprotein IIb/IIIa receptors.
- Developed a novel contrast agent: microparticles of iron oxide (MPIOs) conjugated to a LIBS-specific antibody (LIBS-MPIO).
- Applied LIBS-MPIO MRI, confocal microscopy, and electron microscopy in Plasmodium berghei-infected mice.
Main Results:
- LIBS-MPIO detected platelet accumulation in the brain microvasculature of infected mice before conventional MRI.
- Tumor necrosis factor-alpha (TNF-alpha) induced platelet adhesion to cerebrovascular endothelium.
- Peak platelet adhesion occurred 12 hours post-TNF-alpha injection and was detectable by LIBS-MPIO MRI.
Conclusions:
- Targeted LIBS-MPIO contrast agents enable noninvasive, in vivo MRI detection of early cerebral malaria.
- This approach facilitates diagnostic, mechanistic, and therapeutic studies for cerebral malaria.
- The method shows potential for detecting pathology before clinical manifestation.
