In vivo characterization of physiological and metabolic changes related to isocitrate dehydrogenase 1 mutation expcression by multiparametric MRI and MRS in a rat model with orthotopically grafted human‐derived glioblastoma cell lines

Abstract

The physiological mechanism induced by the isocitrate dehydrogenase 1 (IDH1) mutation, associated with better treatment response in gliomas, remains unknown.The aim of this preclinical study was to characterize the IDH1 mutation through in vivo multiparametric MRI and MRS. Multiparametric MRI, including the measurement of blood flow, vascularity, oxygenation, permeability, and in vivo MRS, was performed on a 4.7 T animal MRI system in rat brains grafted with human-derived glioblastoma U87 cell lines expressing or not the IDH1 mutation by the CRISPR/Cas9 method, and secondarily characterized with additional ex vivo HR-MAS and histological analyses. In univariate analyses, compared with IDH1−, IDH1+ tumors exhibited higher vascular density (p < 0.01) and better perfusion (p = 0.02 for cerebral blood flow), but lower vessel permeability (p < 0.01 for time to peak (TTP), p = 0.04 for contrast enhancement) and decreased T 1 map values (p = 0.02). Using linear discriminant analysis, vascular density and TTP values were found to be independent MRI parameters for characterizing the IDH1 mutation (p < 0.01). In vivo MRS and ex vivo HR-MAS analysis showed lower metabolites of tumor aggressiveness for IDH1+ tumors (p < 0.01). Overall, the IDH1 mutation exhibited a higher vascularity on MRI, a lower permeability, and a less aggressive metabolic profile. These MRI features may prove helpful to better pinpoint the physiological mechanisms induced by this mutation.

Multi-tracer and multiparametric PET imaging to detect the IDH mutation in glioma: a preclinical translational in vitro, in vivo, and ex vivo study

“…The lower tracer uptake values are consistent with the reduced level of neuroinflammation and by extension the decreased aggressiveness of IDH+ tumors, which is in complete accordance with reports from the literature [ 38 , 42 ]. Our recent study, which investigated multiparametric MRI, also found a spectroscopic profile of lower aggressiveness for IDH+ tumors, which further confirms results obtained in the current study [ 28 ]. Other mechanisms related to the IDH mutation may be suggested albeit based on assumptions that cannot be substantiated from our current data.…”

“…Blood brain barrier (BBB) penetrance remains an issue for TSPO imaging [ 22 ] but is not a limitation for brain tumors in general or for gliomas per se since the brain blood barrier is disrupted in the vast majority of HGGs. Our previous study showed that contrast-enhancements were observed in our animal models, confirming that the BBB was disrupted [ 28 ]. In any case, our current study underlines the fact that using multiparametric PET, i.e.…”

“…U87 human derived HGG cell lines IDH1 -mutated (IDH1+) and non IDH1 -mutated (IDH1-) were purchased from the American Type Culture Collection® (ATCC, HTB-14IG and HTB-14). The two cells lines were cultured under standard conditions as previously described [ 28 ].…”

“…IDH1+ and IDH1- cells (5 × 10 4 cells per animal) were implanted into the right caudate nucleus of the brain of athymic male nude rats (200–250 g; RH-Foxn1rnu; Envigo Gannat, France) as previously described [ 28 ].…”

“…This innovative genetic approach allows to evaluate the effects of the isolated, basal expression of the IDH1 mutation. We previously characterized in vivo physiologic and metabolic changes of the IDH1 mutation using multiparametric MRI and spectroscopy [ 28 ]. Such multiple MRI sequences are nevertheless difficult to apply in clinical routine practice which underpins the recent interest in currently available PET radiotracers, particularly radiotracers specific for inflammation and metabolism, that may be able to inform about additional tumor properties and more targeted pathophysiological mechanisms.…”