M-1551. Non-invasive (NI) Measurement of Blood-Brain-Barrier (BBB) Disruption in Cryptococcal Meningoencephalitis (CNME)
Session: Poster Session: Experimental Mycology
Sunday, October 26, 2008: 12:00 AM
Room: Hall C
Background: Development of brain lesions due to CNME is associated with poor prognosis in HIV patients (PLoS ONE 2008;3(4):e1950). We evaluated the role of gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) as a NI biomarker of BBB disruption using magnetic resonance imaging (MRI) in a rat model of CNME. Methods: A 48-hour (H) culture of Cryptococcus neoformans (CN) serotype A [ATCC 208821, H99] was used to generate an inoculum of 108 colony forming units (CFU)/mL. A 0.1 mL (107 CFU) inocula were injected into five male 250-300 g Fischer F344 rats via the lateral tail vein. MRI was performed at baseline (pre-infection) and on day 4 post-infection using a 4.7T Biospec® MRI scanner with a small bore linear radiofrequency coil. MRI studies at baseline included T2-weighted-3 dimensional rapid acquistion with relaxation enhancement. This structural imaging protocol was repeated on day 4 along with a multiple graphical analysis (MGA) method. The MGA protocol included bolus intravenous injection via a catheter of 0.2 mM/kg of Gd-DTPA with a rapid T1 mapping protocol of 14 time-points over 45 minutes. Apparent diffusion coefficient (ADC) and permebaility coefficient (PC) maps were generated and compared within rats using the paired t-test. Rats were sacrificed on day 5, and brain histology of the optic chiasm, pons, and cerebellum were compared to MRI data. Results: All rats had formation of numerous brain lesions on day 4 noted by high signal intensity on T2-weighted images. The average ADC values were 39% higher (p<0.05) on day 4 relative to baseline. The mean ± SD PC was significantly (p<0.05) higher within lesions 2.06 ± 0.42 mL/(g*min) compared to normal tissue 0.34 ± 0.10 mL/(g*min). Brain histology matched MRI data with demonstration of classic ‘soap-bubble’ non-inflammatory cystic lesions that were filled with CN. Conclusions: CNME disrupts rat BBB and is detectable by Gd-DTPA enhanced MRI. This suggests that novel antifungals agents with high molecular weights should not be discounted as possible treatments of CNME.
Manjunath Pai, PharmD1, Rohit Sood2, Unal Sakoglu2 and  M. P. Pai, None., (1)University of New Mexico, Albuquerque, NM, (2)University of New Mexico


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