Low-grade glioma: correlation of short echo time 1H-MR spectroscopy with 23Na MR imaging

BACKGROUND AND PURPOSE: There is considerable variability in the clinical behavior and treatment response of low-grade (WHO grade II) gliomas. The purpose of this work was to characterize the metabolic profile of low-grade gliomas by using short echo time ¹H-MR spectroscopy and to correlate metabolite levels with MR imaging-measured sodium (²³Na) signal intensity. Based on previous studies, we hypothesized decreased N-acetylaspartate (NAA) and increased myo-inositol (mIns), choline (Cho), glutamate (Glu), and ²³Na signal intensity in glioma tissue.MATERIALS AND METHODS: Institutional ethics committee approval and informed consent were obtained for all of the subjects. Proton (¹H-MR) spectroscopy (TR/TE = 2200/46 ms) and sodium (²³Na) MR imaging were performed at 4T in 13 subjects (6 women and 7 men; mean age, 44 years) with suspected low-grade glioma. Absolute metabolite levels were quantified, and relative ²³Na levels were measured in low-grade glioma and compared with the contralateral side in the same patients. Two-sided Student t tests were used to test for statistical significance.RESULTS: Significant decreases were observed for NAA (P < .001) and Glu (P = .004), and increases were observed for mIns (P = .003), Cho (P = .025), and sodium signal intensity (P < .001) in low-grade glioma tissue. Significant correlations (r² > 0.25) were observed between NAA and Glu (P < .05) and between NAA and mIns (P < .01). Significant correlations were also observed between ²³Na signal intensity and NAA (P < .01) and between ²³Na signal intensity and Glu (P < .01). Ratios of NAA/mIns, NAA/²³Na, and NAA/Cho were altered in glioma tissue (P < .001); however based on the t statistic, NAA/²³Na (t = 9.6) was the most significant, followed by NAA/mIns (t = 6.1), and NAA/Cho (t = 5.0).CONCLUSION: Although Glu concentration is reduced and mIns concentration is elevated in low-grade glioma tissue, the NAA/²³Na ratio was the most sensitive indicator of pathologic tissue.

Low-grade (WHO grade II) gliomas, including astrocytoma, oligodendroglioma, and mixed glioma (oligoastrocytoma), account for 10%–20% of primary brain tumors in adults.¹ Although such tumors are more indolent than high-grade gliomas, there is considerable variability in their clinical behavior.² They are capable of malignant transformation and, ultimately, are almost universally fatal. Pathologically, these tumors are diffuse and infiltrative but lack such anaplastic features as necrosis, endothelial proliferation, and mitotic activity.³Tailoring treatment to the individual patient requires a better understanding of the factors that account for the variability in tumor behavior.^{4, 5} Currently, neither the appearance of a low-grade glioma on conventional MR imaging nor tumor pathology can completely predict future tumor behavior or response to treatment. Metabolic profiling of these tumors with MR spectroscopy has the potential to improve our ability to predict the biological behavior and treatment response of low-grade gliomas and to better delineate tumor boundaries. Previous in vitro and in vivo MR spectroscopy studies have identified metabolic markers that help noninvasively discriminate tumor type,^6–8 aid in radiation treatment planning,⁹ or predict survival.¹⁰ Most studies have used long echotime spectroscopy acquisitions (TE ≥ 130 ms), limiting tumor metabolite characterization to the dominant peaks in the ¹H spectrum: N-acetylaspartate (NAA; a putative marker of neuronal viability), total creatine (Cr; involved in energy metabolism), choline-containing compounds (Cho; associated with membrane breakdown/synthesis), and lactate (associated with anaerobic glycolysis). Typically, low-grade glioma is characterized by reduced NAA due to reduced neuronal attenuation, reduced Cr due to a hypermetabolic state, and increased Cho, reflecting increased membrane turnover.^{6, 8} The metabolites glutamate (Glu) and myo-inositol (mIns), measurable by shorter echotime ¹H-MR spectroscopy, may provide additional information about the pathologic state of the neoplasm. A previous study¹¹ has demonstrated that highly malignant tumors may release excess Glu to kill surrounding tissue and promote tumor growth, and increased Glu plus glutamine (Gln) has been measured previously in oligodendroglioma by ¹H-MR spectroscopy.¹² mIns activation of protein kinase C¹³ has also been associated with tumor malignancy. The limited use of short echotime ¹H-MR spectroscopy is due mainly to the difficulty in quantifying metabolites with complicated j-modulated spectral line shapes and the uncertainty introduced by less well-characterized macromolecule resonances beneath the metabolites of interest.Tumors may also be characterized by the local concentration of total sodium, which is sensitive to changes in the tumor microstructure.^14–16 For example, neoplastic cell proliferation and packing, cell death, and necrosis expand the extracellular space in tumors. A defective blood-brain barrier in tumors also permits water, electrolytes, and proteins to enter the extracellular space leading to vasogenic edema. Because both intracellular and extracellular sodium levels may be increased in tumors, ²³Na MR imaging represents a potentially sensitive and noninvasive means of monitoring tissue sodium content related to cancer pathology.^15–18The purpose of this study was to prospectively characterize the metabolic profile of low-grade gliomas by using ¹H-MR spectroscopy and to correlate metabolite levels with MR imaging-measured sodium signal intensity. Based on previous studies, it was hypothesized that levels of NAA would be reduced, and levels of Cho, mIns, Glu, and ²³Na signal intensity would be increased in low-grade glioma compared with normal tissue.