Metabolism of diffuse intrinsic brainstem gliomas in children

Abstract

Progress in the development of effective therapies for diffuse intrinsic brainstem gliomas (DIBSGs) is compromised by the unavailability of tissue samples and the lack of noninvasive markers that can characterize disease status. The purpose of this study was to compare the metabolic profile of DIBSGs with that of astrocytomas elsewhere in the CNS and to determine whether the measurement of metabolic features can improve the assessment of disease status. Forty in vivo MR spectroscopy (MRS) studies of 16 patients with DIBSG at baseline and after radiation therapy were retrospectively reviewed. Control data for baseline studies of DIBSGs were obtained from 14 untreated regular and anaplastic astrocytomas. All spectra were acquired with single-voxel, short echo-time (35 ms), point-resolved spectroscopy. Absolute metabolite concentrations (mmol/kg) and lipid intensities (arbitrary units) were determined. At baseline, creatine and total choline (tCho) were significantly lower in DIBSGs than in astrocytomas elsewhere in the CNS (4.3 +/- 1.1 vs. 7.5 +/- 1.9 mmol/kg, p < 0.001; 1.9 +/- 0.7 vs. 4.2 +/- 2.6, p < 0.001). Serial MRS in individual subjects revealed increasing levels of tCho (p < 0.05) and lipids (p < 0.05) and reduced ratios of N-acetylaspartate, creatine, and myoinositol relative to tCho (all p < 0.01). Metabolic progression defined by increased tCho concentration in serial MRS preceded clinical deterioration by 2.4 +/- 2.7 months (p < 0.04). Low tCho of DIBSG at baseline is consistent with low proliferative tumors. Subsequent metabolic changes that have been associated with malignant degeneration preceded clinical deterioration. MRS provides early surrogate markers for disease progression.

Fig. 1

Proton MR spectroscopy (1H MRS) of untreated diffuse intrinsic brainstem glioma (DIBSG), astrocytoma, and control. MR spectra and corresponding T2-weighted transverse fast spin-echo MRI (3,500/85 [repetition time/echo time, ms], 256 × 192 matrix, two signals acquired, echo train length of 16, acquisition time of 2 min 48 s) indicating the regions of interest for MRS are shown. Shown are the unfiltered raw data (gray line) and the fit to the data used for quantitation (black line). (A) A representative spectrum of DIBSG shows small lactate (Lac) peaks, residual N-acetylaspartate (NAA), the complex signal stemming from glutamate (Glu) and glutamine (Gln), total choline (tCho) only slightly exceeding creatine (Cr), and prominent myoinositol (mI). (B) Lipids were prominent in only one DIBSG patient (Pt 8; compare Fig. 2). (C, D) Representative spectra from astrocytoma and normal brainstem are shown for comparison. Note that Lac with two narrow peaks of equal amplitudes centered at 1.3 ppm can be discerned from broad lipid resonances (LipMM13, lipid signal at 1.3 ppm; LipMM09, lipid signal at 0.9 ppm). All spectra are scaled according to measured absolute concentrations to allow direct comparison of peak areas. Underlying broad resonances from macromolecules may contribute to the lipid signal.

Fig. 2

Total choline (tCho) and lipids of diffuse intrinsic brainstem glioma (DIBSG) at baseline. In this study, mean tCho of DIBSG at baseline was reduced when compared with regular astrocytoma (A) and anaplastic astrocytoma (AA) elsewhere in the CNS or with normal control brainstem. Also, only one patient (Pt 8) showed prominent lipids at initial presentation. DIBSG clustered at low tCho concentrations and lipid intensities. Abbreviations: LipMM13, lipid signal at 1.3 ppm; a.u., arbitrary units.

Fig. 3

Correlation of metabolic features at baseline with survival. Increasing total choline (tCho) and lipids as well as decreasing creatine/tCho (Cr/tCho) and N-acetylaspartate/tCho (NAA/tCho) ratios have been associated with increasing malignancy. These features may thus identify already progressed lesions at presentation with possibly particularly poor prognosis; however, Spearman rank correlation analysis did not reveal that these or any other metabolic measures were significantly associated with survival when all data were pooled (A–D). Data points for patient 6 (Pt 6) are labeled as the time courses of metabolite concentrations and lipid intensities (LipMM13, lipid signal at 1.3 ppm) were notably different in this patient (compare to Fig. 5).

Fig. 4

Serial MRI and MR spectroscopy (MRS) of a representative diffuse intrinsic brainstem glioma (DIBSG) patient. Transverse postcontrast T1-weighted fluid-attenuated inversion recovery MRI (repetition time/echo time/ inversion time = 2,000/7/750, matrix size = 256 × 256, number of excitations = 1, echo train length = 6, acquisition time = 2 min 8 s), T2-weighted MRI, and MRS of patient 3 with typical clinical course. The metabolic progression observed in this patient was representative for most patients (not for patient 6; compare Fig. 5) with typical clinical course. Lesion volume on MRI decreased from initial 259 cm³ to 146 cm³ after therapy at 2.5 months and then further to 115 cm³ at 4.7 months. At that time it was noted that MRS, with increased total choline (tCho), lipids, and reduced creatine/ tCho (Cr/tCho), was suggestive of disease progression. A ring-enhancing lesion detected at 2.5 months was not observed at 4.7 months. Clinical and radiological deterioration occurred at 6.5 months; this patient died 11 months after initial diagnosis. Spectra are scaled to measured concentrations to allow direct comparison of peak areas. Abbreviations: mI, myoinositol; Glu, glutamate; Gln, glutamine; NAA, N-acetylaspartate; Lac, lactate; LipMM13, lipid signal at 1.3 ppm; LipMM09, lipid signal at 0.9 ppm.

Fig. 5

Serial MR spectroscopy (MRS) of patient 6 (Pt 6), who had noticeably different metabolite and lipid time courses. In contrast to other patients, all metabolites, including total choline (tCho), decreased after therapy, while lipids increased. This is consistent with therapy-induced cell death and the release of intracellular metabolites and the generation of fatty acids and lipids from membrane degeneration. Lipid levels and metabolites returned to baseline levels at 7 months, consistent with regrowing tumor. A T2-weighted MR image acquired at the time of diagnosis indicating the region of interest is shown. Abbreviations: Pre-Tx, pre-treatment; Cr, creatine; mI, myoinositol; LipMM13, lipid signal at 1.3 ppm; LipMM09, lipid signal at 0.9 ppm; Glu, glutamate; Gln, glutamine; NAA, N-acetylaspartate; Lac, lactate.

Fig. 6

(A – E) MR spectroscopy (MRS)/MRI of patient 14. MRS of this atypical long-term survivor revealed a marked accumulation of lipids in the lesion after radiation therapy several hundred standard deviations above levels observed in other treated diffuse intrinsic brainstem gliomas (DIBSGs). Lipid accumulation peaked approximately 1 year after therapy and decreased thereafter. (D) At 21 months, two spectra were acquired. One was obtained from the main lesion (DI) and a second one from a newly detected focus adjacent to the main lesion (DII). (E) When spectrum DII was scaled up by a factor of 40 (lipids truncated for clarity), prominent choline relative to creatine (Cr) was detected. (F) Twenty-three months after initial diagnosis, lipid levels declined noticeably and the total choline (tCho) peak was more readily detected. This patient relapsed at that time and died 28 months after initial diagnosis. (A) T2-weighted fast-spin echo MRI is shown. Postcontrast (C) and precontrast (E) MRIs (T1-weighted fluid-attenuated inversion recovery [repetition time/echo time/inversion time = 2,000/7/750, matrix size 256 × 256, number of excitations = 1, echo train length = 6, acquisition time = 2 min 8 s]) are also shown. The main lesion did not show apparent differences on pre – or post – T1-weighted MRIs in those studies. Spectra are scaled to measured lipid intensities to allow direct comparison of peak areas. Abbreviations: RTx, radiation therapy; LipMM13, lipid signal at 1.3 ppm; LipMM09, lipid signal at 0.9 ppm.

Fig. 7

MR spectroscopy (MRS) of atypical long-term survivors (patients 7 [Pt 7] and 16 [Pt 16]). (A) Baseline MRS of patient 7 is comparable with what has been observed in the majority of patients with diffuse intrinsic brainstem glioma (DIBSG) at baseline (compare Figs. 1 and 4). (B) MRS studies of patient 16, who lived longest of all patients, were carried out only at the very late disease stage at the time of relapse. At that time, the spectral profile resembled that of progressed disease with prominent lipids and high total choline (tCho). Abbreviations: mI, myoinositol; Cr, creatine; Glu, glutamate; Gln, glutamine; Lac, lactate; LipMM13, lipid signal at 1.3 ppm; LipMM09, lipid signal at 0.9 ppm.