Assessing the predictability of IDH mutation and MGMT methylation status in glioma patients using relaxation-compensated multipool CEST MRI at 7.0 T

Abstract

Background: Early identification of prognostic superior characteristics in glioma patients such as isocitrate dehydrogenase (IDH) mutation and O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation status is of great clinical importance. The study purpose was to investigate the non-invasive predictability of IDH mutation status, MGMT promoter methylation, and differentiation of low-grade versus high-grade glioma (LGG vs HGG) in newly diagnosed patients employing relaxation-compensated multipool chemical exchange saturation transfer (CEST) MRI at 7.0 Tesla.

Methods: Thirty-one patients with newly diagnosed glioma were included in this prospective study. CEST MRI was performed at a 7T whole-body scanner. Nuclear Overhauser effect (NOE) and isolated amide proton transfer (APT; downfield NOE-suppressed APT = dns-APT) CEST signals (mean value and 90th signal percentile) were quantitatively investigated in the whole tumor area with regard to predictability of IDH mutation, MGMT promoter methylation status, and differentiation of LGG versus HGG. Statistics were performed using receiver operating characteristic (ROC) and area under the curve (AUC) analysis. Results were compared with advanced MRI methods (apparent diffusion coefficient and relative cerebral blood volume ROC/AUC analysis) obtained at 3T.

Results: dns-APT CEST yielded highest AUCs in IDH mutation status prediction (dns-APTmean = 91.84%, P < 0.01; dns-APT90 = 97.96%, P < 0.001). Furthermore, dns-APT metrics enabled significant differentiation of LGG versus HGG (AUC: dns-APTmean = 0.78, P < 0.05; dns-APT90 = 0.83, P < 0.05). There was no significant difference regarding MGMT promoter methylation status at any contrast (P > 0.05).

Conclusions: Relaxation-compensated multipool CEST MRI, particularly dns-APT imaging, enabled prediction of IDH mutation status and differentiation of LGG versus HGG and should therefore be considered as a non-invasive MR biomarker in the diagnostic workup.

Figures

Fig. 1

Predictability of WHO tumor grade (HGG vs LGG) in newly diagnosed untreated glioma. (A, B) dns-APT allowed prediction of WHO tumor grade with highest AUC for the dns-APT90 metric (0.83) and a test sensitivity/specificity of 0.63 (0.41–0.81)/1.00 (0.48–1.00) (P < 0.05). Two exemplary patients with HGG (GBM, c1–g1) and LGG (oligodendroglioma II, c2–g2) shown: ci: GdCE T1-w, di: T2-w (TSE), relaxation-compensated multipool CEST MRI at 7T with separated APT (ei), NOE (fi), and dns-APT (gi) effects (unit: %). The GBM patient shows only a small spot-like contrast enhancement in the tumor region (c1), while a clear hyperintensity displays within the tumor at dns-APT imaging (g1, white arrow).

Fig. 2

Predictability of IDH mutation status (IDH1-R132H wt versus mutation) in newly diagnosed untreated glioma. (A, B) APT and dns-APT CEST metrics allowed prediction of IDH mutation status with highest AUC for the dns-APT90 metric (0.98) with a test sensitivity/specificity of 0.95 (0.77–1.00)/1.00 (0.59–1.00) (P < 0.0001). Two exemplary patients with newly diagnosed GBM IDH-wt (c1 –g1) and IDH-mut (c2 –g2) shown: ci: GdCE T1-w, di: T2-w (TSE), relaxation-compensated multipool CEST MRI at 7T with separated APT (ei), NOE (fi), and dns-APT (gi) effects (unit: %). A ring-like hyperintensity can be delineated in the periphery of the IDH-wt glioblastoma at dns-APT imaging (g1, white arrow), while the IDH-mut GBM displays barely hyperintense at dns-APT (g2, white arrow). The head of the caudate nucleus also displays hyperintense on dns-APT images (g2, pink arrows).

Fig. 3

Predictability of MGMT promoter methylation status (unmethylated vs methylated) in newly diagnosed untreated glioma patients. (A, B) None of the investigated CEST contrasts allowed for significant prediction of the MGMT promoter methylation in glioma patients. Two GBM patients with unmethylated (GBM MGMT−: c1–g1) and methylated (GBM MGMT+: c2–g2) promoter shown: ci: GdCE T1-w, di: T2-w (TSE), relaxation-compensated multipool CEST MRI at 7T with separated APT (ei), NOE (fi), and dns-APT (gi) effects (unit: %). A tendency toward higher signal intensities for patients with unmethylated MGMT promoter was observed for all investigated CEST contrasts.