Gadolinium- and 5-Aminolevulinic Acid-Induced Protoporphyrin IX Levels in Human Gliomas: An Ex Vivo Quantitative Study to Correlate Protoporphyrin IX Levels and Blood-Brain Barrier Breakdown

Abstract

In recent years, 5-aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) fluorescence guidance has been used as a surgical adjunct to improve the extent of resection of gliomas. Exogenous administration of ALA before surgery leads to the accumulation of red fluorescent PpIX in tumor tissue that the surgeon can visualize and thereby discriminate between normal and tumor tissue. Selective accumulation of PpIX has been linked to numerous factors, of which blood-brain barrier breakdown has been suggested to be a key factor. To test the hypothesis that PpIX concentration positively correlates with gadolinium (Gd) concentrations, we performed ex vivo measurements of PpIX and of Gd using inductively coupled plasma mass spectrometry, the latter as a quantitative biomarker of blood-brain barrier breakdown; this was corroborated with immunohistochemistry of microvascular density in surgical biopsies of patients undergoing fluorescence-guided surgery for glioma. We found positive correlations between PpIX concentration and Gd concentration (r = 0.58, p < 0.0001) and between PpIX concentration and microvascular density (r = 0.55, p < 0.0001), suggesting a significant, yet limited, association between blood-brain barrier breakdown and ALA-induced PpIX fluorescence. To our knowledge, this is the first time that Gd measurements by inductively coupled plasma mass spectrometry have been used in human gliomas.