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Characterization of BBB permeability in a preclinical model of cryptococcal meningoencephalitis using magnetic
Manjunath P Pai1, Unal Sakoglu, Steven L Peterson
1College of Pharmacy, University of New Mexico, Albuquerque, New Mexico, USA.
Abstract:
Cryptococcus neoformans meningoencephalitis (CNME) is a leading fungal cause of death among acquired immunodeficiency syndrome patients. Innovative preclinical systems that permit high throughput in vivo evaluation of novel agents are desperately needed. Magnetic resonance imaging (MRI) was evaluated as a tool to develop a rat model of CNME and to quantify noninvasively blood-brain barrier (BBB) disruption secondary to this disease. The aim of this study was to identify MRI changes compared with histopathology and fungal burden measurements as potential biomarkers. A well-characterized strain of C neoformans (CN) var grubii was used to infect rats using intravenous inoculation. An inoculum-finding study was performed by infecting rats with 10(3), 10(5), and 10(7) colony-forming units (CFUs). Animals underwent dynamic MRI on days 4 and 7 after inoculation. An inoculum-confirming study was performed by infecting rats with 10(5), 10(6), and 10(7) CFU and fungal burden was determined in the brain, lung, and spleen. Animals infected with 10(7) CFU of CN developed lesions that appeared hyperintense on T2-weighted images on day 4. The histopathology results correlated well with MRI data. Diffusion weighted and permeability estimates were 1.4 and 6.1-fold higher, respectively, in lesions compared with healthy tissue. Magnetic resonance imaging is a promising preclinical tool to evaluate effects of antifungal and adjunctive agents.
Insights
Magnetic resonance imaging (MRI) offers a promising preclinical tool for evaluating new antifungal treatments in a rat model of Cryptococcus neoformans meningoencephalitis (CNME). MRI can noninvasively detect blood-brain barrier disruption and disease progression, correlating well with histopathology.
Area of Science:
- Neuroscience
- Infectious Diseases
- Medical Imaging
Background:
- Cryptococcus neoformans meningoencephalitis (CNME) is a significant cause of mortality in AIDS patients.
- There is a critical need for high-throughput preclinical systems to evaluate novel antifungal agents in vivo.
- Magnetic resonance imaging (MRI) offers potential for noninvasive disease monitoring.
Purpose of the Study:
- To develop a rat model of CNME using Magnetic Resonance Imaging (MRI).
- To quantify blood-brain barrier (BBB) disruption noninvasively using MRI.
- To identify MRI changes as potential biomarkers correlating with histopathology and fungal burden.
Main Methods:
- Rats were infected intravenously with Cryptococcus neoformans (CN) var grubii.
- Dynamic MRI was performed on days 4 and 7 post-inoculation.
- Histopathology and fungal burden in brain, lung, and spleen were determined.
Main Results:
- Infection with 10(7) CFU of CN induced T2-hyperintense lesions by day 4.
- MRI findings correlated well with histopathology.
- Diffusion weighted and permeability estimates were significantly higher in lesions compared to healthy tissue.
Conclusions:
- MRI is a valuable preclinical tool for developing a rat model of CNME.
- MRI can noninvasively assess BBB disruption in CNME.
- MRI shows promise for evaluating the efficacy of antifungal and adjunctive therapies.
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