Introduction: The blood-brain barrier (BBB) is a significant obstacle in the treatment of malignant brain lesions (1,2). The BBB can prevent drugs from entering the brain, and it is theorized that when significantly compromised, drugs may also be cleared from the brain rapidly, lowering their therapeutic effect. The neurovascular unit, which helps comprise this barrier, is known to be composed of the endothelial cells of the brain microvasculature together with pericytes and astrocyte foot processes (3). We hypothesized that by examining the relationship between glial fibrillary acidic protein (GFAP), Aquaporin 4 (AQ4) to examine the astrocytic foot processes (4, 5), and CD31, we would note a significant breakdown in the organization of the neurovascular unit in enhancing lesions.

Methods: Paraffin-embedded samples taken from 12 consecutive patients who underwent surgery for malignant lesions of the brain were examined by double immunofluorescence. All patients underwent pre-operative contrast-enhanced T1-weighted magnetic resonance imaging. There were three non-enhancing lesions, two Grade II astrocytomas and one Grade III astrocytomas. There were 9 enhancing lesions, four GBMs, three metastases and two Grade III astrocytomas. Two samples were examined from each patient, one double stained for GFAP and CD31 and another with AQ4 and CD31.

Results: The non-enhancing lesions and peri-tumoral areas in the enhancing lesions showed well-organized perivascular glial processes with tight orientation of GFAP and AQ4 staining along the CD31-positive vessels. Enhancing glial lesions showed disorganized staining of the glial processes with no clear organization of the neurovascular unit and diffuse GFAP and AQ4 staining. Metastases showed a lack of GFAP or AQ4 staining within the bulk of the tumor with no glial processes associated with the CD31-positive vasculature.

Conclusions: Enhancing lesions exhibit a disorganized neurovascular unit lacking perivascular glial processes, contributing to the breakdown of the BBB at these sites.

Patient Care: By further understanding the differences between the functioning of the blood-brain barrier in different malignant brain lesions, we can better plan the drug delivery of therapeutic agents to these lesions

Learning Objectives: By the conclusion of this session, participants should be able to: 1) describe the components of a functioning blood-brain barrier 2) recognize the morphology of the glial processes in the blood-brain barrier 3) appreciate the changes in the structure of the neurovascular unit in enhancing lesions

References: 1. Papadatos-Pastos, D. and U. Banerji, Revisiting the role of molecular targeted therapies in patients with brain metastases. J Neurooncol, 2011. 2. Ding, D., C.W. Kanaly, D.D. Bigner, et al., Convection-enhanced delivery of free gadolinium with the recombinant immunotoxin MR1-1. J Neurooncol, 2010. 98(1): p. 1-7. 3. Abbott, N.J., L. Ronnback, and E. Hansson, Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci, 2006. 7(1): p. 41-53. 4. Nagelhus, E.A., T.M. Mathiisen, and O.P. Ottersen, Aquaporin-4 in the central nervous system: cellular and subcellular distribution and coexpression with KIR4.1. Neuroscience, 2004. 129(4): p. 905-13. 5. Warth, A., P. Simon, D. Capper, et al., Expression pattern of the water channel aquaporin-4 in human gliomas is associated with blood-brain barrier disturbance but not with patient survival. J Neurosci Res, 2007. 85(6): p. 1336-46.