Multiparametric Imaging Analysis




Magnetic resonance spectroscopy (MRS) is a magnetic resonance–based imaging modality that allows noninvasive sampling of metabolic changes in normal and abnormal brain parenchyma. MRS is particularly useful in the differentiation of developmental or non-neoplastic disorders from neoplastic processes. MRS is also useful during routine imaging follow-up after radiation treatment or during antiangiogenic treatment and for predicting outcomes and treatment response. The objective of this article is to provide a concise but thorough review of the basic physical principles, important applications of MRS in brain tumor imaging, and future directions.


Key points








  • Magnetic resonance spectroscopy (MRS) is a noninvasive technique that allows the study of metabolic processes and chemical environment in the brain parenchyma.



  • MRS is one of the few diagnostic techniques that can be used for evaluation of low-grade neoplastic processes and for their differentiation from non-neoplastic entities.



  • Despite many technical and reimbursement challenges to its use in routine clinical practice, MRS will continue to develop as an important and sensitive imaging tool for assessment of intracranial pathologies.






Discussion of problem/clinical presentation


MRS allows the qualitative and quantitative assessment of specific metabolites in the brain parenchyma or intracranial extra-axial spaces. MRS analysis of brain tumors can be performed using 1 H (proton) MRS or, less frequently, with 31 P (phosphorus) or 13 C (carbon) MRS techniques. For 1 H MRS, the most common metabolites evaluated in routine clinical practice include N -acetyl aspartate (NAA), choline-containing compounds (Cho), creatine (Cr), myo-inositol (mI), lipid (Lip), and lactate (Lac) ( Table 1 ). NAA is considered a neuronal metabolite and is decreased in processes with neuronal destruction or dysfunction. Cr is a metabolite related to the cellular energy metabolism and is considered relatively stable in different pathologic processes affecting the central nervous system and useful as a reference metabolite. Cho are related to membrane turnover and their elevation is indicative of a process that results in increased glial proliferation and membrane synthesis (as seen with cellular proliferative disorders). Lip peaks are often indicative of areas of necrosis and Lac peaks are directly originated from processes resulting in anaerobic metabolism. mI can be a marker of astrocytic metabolism and can be seen elevated in certain pathologic processes (see Table 1 ).



Table 1

Metabolites evaluated with magnetic resonance spectroscopy in brain tumor imaging


















































































Metabolite Peak Configuration Resonance (ppm) Best Echo Time for Detection Clinical Associations
NAA Singlet 2.0 Short or long TE Neuronal marker (not seen in non-neural brain tumors)
Cho Singlet 3.22 Short or long TE Membrane turnover marker and cellular proliferation
Cr Singlets 3.03 and 3.9 Short or long TE Cellular energy byproduct. Lower in necrosis
mI Multiplets 3.56 Short TE Low-grade gliomas, gliomatosis
Lip Broad peaks 0.9, 1.3 Short TE Tuberculomas, PCNSL, radiation necrosis
Lac Doublet 1.33 1.5T = inverted at 135–144 ms
3T = 288 ms
Anaerobic metabolism marker Prominent if necrosis or hypoxia
Glx Multiplets 2.1–2.4 ppm; 3.7 ppm Short TE Detected in GBM, astrocytomas and oligodendrogliomas
Taurine Triplets 3.4 Short TE Medulloblastomas
Alanine Doublet 1.47 1.5 T = 144 ms Meningiomas
Citrate Multiplets 2.6 3T = 35 ms and inverts at 97 ms Gliomas, particularly aggressive pediatric types
Gly Singlet 3.55 3T = 160 ms Low-grade gliomas, central neurocytomas
2HG Multiplets 1.85, 2.01, 2.28, and 4.05 Best seen with spectral editing techniques
3T = 97 ms
IDH mutations

Adapted from Chronaiou I, Stensjoen AL, Sjobakk TE, et al. Impacts of MR spectroscopic imaging on glioma patient management. Acta Oncol 2014;53(5):583.


Common diagnostic problems encountered in routine clinical brain tumor imaging can be summarized as follows.


Is It Neoplastic or Not?


Non-neoplastic processes, including malformations of cortical development (such as focal cortical dysplasia) ( Fig. 1 ), hamartomas, cerebral infarcts, infectious pathologies, inflammatory diseases (including demyelinating and vasculitic processes), and vascular pathologies (including capillary telangiectasias and cavernous malformations), can be difficult to differentiate from intra-axial or extra-axial intracranial neoplastic processes in conventional magnetic resonance (MR) studies ( Table 2 ). MRS is a useful imaging tool to help in the differentiation and characterization of these pathologies. Neoplastic processes have metabolic byproducts related to their mitotic activity (Cho) and neuronal dysfunction (NAA) that can be detected by MRS and improve the accuracy of the clinical diagnosis ( Fig. 2 ). The closer the MR spectrum is to a normal spectrum the more likely that the intracranial lesion is a benign process or developmental anomaly (see Fig. 1 ). There is significant overlap in the Cho/NAA ratios, however, between non-neoplastic processes, such as tumefactive demyelinating lesions, infarcts, and infectious processes with neoplastic pathologies. Specific metabolic markers have been identified that may make this distinction more reliable (eg, glutamate/glutamine [Glx] for demyelination or 2-hydroxyglutarate [2HG] for isocitrate dehydrogenase [IDH] 1–mutant gliomas).




Fig. 1


Focal cortical dysplasia. A 13-year-old male patient presenting with nocturnal generalized seizures. Coronal ( A ) and axial ( D ) FLAIR images, axial T2-weighted images with corresponding intermediate (TE = 144 ms) TE spectra of a right parietal cortical dysplasia ( B , C ) and contralateral normal brain parenchyma ( E , F ). There is no significant difference in the metabolite ratios between the lesion compared with the ipsilateral surrounding and contralateral brain parenchyma. The yellow arrows point to the lesion.


Table 2

Magnetic resonance spectroscopy features of intracranial neoplastic and non-neoplastic pathologies






















































































































































































































Pathology N -Acetyl Aspartate Choline Myo-inositol Glutamate/Glutamine Glycine Lactate Lipid Taurine Alanine Amino Acids Succinate 2-Hydroxyglutarate Comments
Glioblastoma and anaplastic gliomas −−/−−− ++/+++ ++ ++ + Necrotic areas with high Lac and Lip
Diffuse astrocytoma + ++ + +
Pilocytic astrocytoma + + + Decreased Cr
Medulloblastoma ++/+++ + +/++ + + +/++ Groups 3 and 4 show high taurine, lower Lip, and high Cr. SHH tumors show high Cho and Lip, with minimal taurine. Also phosphocholine
Ependymoma ++/+++ + Also glycerophosphocholine in vitro
Intracranial metastases −− ++ ++ Relatively normal metabolites in the parenchyma surrounding the lesion
Absent NAA within the lesion
PCNSL +++ MRS obtained from non-necrotic lesions
Epidermoid cysts ++ + + Aminoacids: valine, isoleucine and glycine
Meningioma −−/−−− ++ + Alanine (up to 90% of cases)
Piogenic abscess −/−− +/++ ++ ++ ++ Aminoacids, Lac, alanine, and acetate
Tuberculoma + ++ + ++ Higher Cho/Cr and mI/Cr in tumors. Also peak at 3.8 ppm, possibly guanidinoacetate
Tumefactive demyelinating lesion (TDL) −/−− +/++ +
Radiation necrosis + ++ ++ Higher Cho/Cr and mI/Cr in tumors



Fig. 2


Low-grade glioma. A 40-year-old woman presenting with partial complex seizures and with a biopsy-proved WHO grade II left insular oligoastrocytoma. Axial FLAIR images with MRS voxels and corresponding intermediate TE spectra from the lesional side ( A , B ) and contralateral side ( C , D ). The white boxes indicate the volume of interest of the obtained spectra, respectively. There is a clear increase of Cho/NAA values within the lesion compared to the contralateral brain parenchyma compatible with the clinical diagnosis of a low-grade glioma.


Is the Lesion a Primary or a Secondary Brain Tumor?


Several studies have shown the utility of MRS, particularly using the multivoxel technique for differentiation of glioblastoma from an intracerebral metastasis. The assessment of normal-appearing brain parenchyma in the immediate vicinity of the tumor has been shown reliable, with glioblastoma cases showing higher Cho/NAA ratios compared with metastatic lesions ( Figs. 3 and 4 ).




Fig. 3


Glioblastoma. A 65-year-old woman presenting with headache and right sided weakness. Pathology was consistent with glioblastoma. Axial FLAIR ( A ), postcontrast axial T1-weighted ( B ), individual spectra (TE = 144 ms) from the anterolateral margin of the enhancing mass ( blue region of interest [ C ]) and contralateral brain ( yellow region of interest [ D ]), spectral map ( E ), and metabolic (Cho/NAA) map ( F ). MR spectra are abnormal even in the adjacent brain parenchyma without conventional MR abnormalities in the left frontal and left parietal lobe. Spectral and metabolic maps clearly depict areas with the highest Cho/NAA ratios providing the best target for proper pathologic grading of the tumor.



Fig. 4


Metastasis. A 90-year-old female patient with history of lung cancer presenting with new visual symptoms and headache. Pathology was consistent with metastatic adenocarcinoma. Axial T1 postcontrast ( A ), MRS grid superimposed on an axial T1 image ( B ), axial FLAIR ( C ), and multivoxel MRS (TE = 144 ms) ( D ). Metabolite ratios are relatively preserved within the areas of vasogenic edema (see voxels 7 and 11).


Is It a High-Grade or Low-Grade Tumor?


Multiple studies have shown the value of MRS for predicting the histologic grade of glial tumors. Higher Cho/NAA ratios have been associated with higher World Health Organization (WHO) grades among glial tumors (see Figs. 2 and 3 ). The Cho/Cr ratio seems more accurate for the differentiation of high-grade versus low-grade gliomas (with sensitivity and specificity values of 80% and 76%, respectively).


Where Is the Best Target for Surgery or Treatment?


MRS can provide a general overview of the metabolic profile of a brain tumor and indicate areas of higher clinical aggressiveness or histologic grade (with higher Cho/Cr ratios). Multivoxel MRS can guide the neurosurgeon for sampling the anatomic sites with the highest histologic grade in low-grade tumors and increases the diagnostic accuracy of stereotactic and excisional biopsies (see Fig. 3 ). There is also growing evidence of the potential use of 3-D volumetric MRS imaging (MRSI) to guide radiation treatment. MRS can potentially identify areas with abnormal Cho/NAA ratios that can extend beyond the tumoral margins defined by conventional MR sequences (see Fig. 3 ).


Radiation-Induced Changes or Recurrent High-Grade Tumor?


MRS, particularly when using multivoxel techniques, has been shown useful for the differentiation of radiation necrosis and recurrent high-grade glioma and recommended as an evidence level II diagnostic modality for this differentiation. In general, areas with recurrent glioma have higher Cho/NAA ratios with variable Lip peaks. Pure radiation necrosis shows prominent Lip with relative decrease of the remaining metabolites compared with the contralateral normal appearing brain parenchyma ( Fig. 5 ). Relative ratios of intralesional Cho to contralateral Cr have also been shown to be a good marker to distinguish between radiation necrosis and recurrent high-grade tumor. This distinction is not always black and white, however, because many cases have concurrent areas of neoplastic involvement and postradiation changes. In addition, elevated Lip can also be seen in high-grade gliomas near areas of central necrosis.




Fig. 5


Radiation necrosis. A 60-year-old male patient with an anaplastic astrocytoma treated with subtotal resection and chemoradiation. Reference axial postcontrast T1-weighted images showing the multivoxel grid ( A ), intralesional single voxel ( B ), and contralateral single voxel ( E ). The multivoxel spectra ( D ) were acquired approximately 6 months after radiation treatment. The single-voxel spectra from the lesion ( C ) and contralateral normal appearing brain parenchyma ( F ) were obtained approximately 1 year after radiation treatment. The lesion progressively decreased in size without treatment. There is diffuse decrease of metabolites within the evaluated areas on the multivoxel spectra and relatively decreased Cho/contralateral Cr ratios on the intralesional single-voxel spectrum compared with the contralateral normal spectrum, compatible with areas of necrosis related to prior radiation.


How to Identify Infiltrative (Recurrent) Tumor in Patients with Glioblastoma Treated with Antiangiogenic Treatment


Patients receiving antiangiogenic medications, such as bevacizumab, show rapid decrease or resolution of the intratumoral abnormal enhancement and the conventional MR sequences are difficult to interpret during the follow-up imaging of these cases. MRS has the potential to identify abnormal metabolic patterns suggestive of tumoral infiltration in progressive areas of fluid-attenuated inversion recovery (FLAIR) hyperintensity in patients treated with bevacizumab, despite the lack of abnormal enhancement. A multicenter trial by the American College of Radiology Imaging Network demonstrated increased NAA/Cho and decreased Cho/Cr levels 8 weeks into the treatment with bevacizumab in patients with recurrent glioblastoma correlated with increased progression free survival rates.


Can Treatment Response or Outcomes Be Predicted with Magnetic Resonance Spectroscopy?


Multiple studies have highlighted the potential role of MRS to predict treatment responses and outcome after treatment. The identification of 2HG in glial tumors with IDH1 mutations and glutamate in pediatric medulloblastomas is associated with better overall survival rates. The decrease of 2HG within glial tumors after treatment also correlate with functional status. MRS, specifically the Lac-to-NAA ratio, may also be helpful in the prediction of potential sites of glioblastoma recurrence. Increased Cho/NAA values 3 weeks after radiation treatment are associated with higher probability of early glioblastoma progression.




Discussion of problem/clinical presentation


MRS allows the qualitative and quantitative assessment of specific metabolites in the brain parenchyma or intracranial extra-axial spaces. MRS analysis of brain tumors can be performed using 1 H (proton) MRS or, less frequently, with 31 P (phosphorus) or 13 C (carbon) MRS techniques. For 1 H MRS, the most common metabolites evaluated in routine clinical practice include N -acetyl aspartate (NAA), choline-containing compounds (Cho), creatine (Cr), myo-inositol (mI), lipid (Lip), and lactate (Lac) ( Table 1 ). NAA is considered a neuronal metabolite and is decreased in processes with neuronal destruction or dysfunction. Cr is a metabolite related to the cellular energy metabolism and is considered relatively stable in different pathologic processes affecting the central nervous system and useful as a reference metabolite. Cho are related to membrane turnover and their elevation is indicative of a process that results in increased glial proliferation and membrane synthesis (as seen with cellular proliferative disorders). Lip peaks are often indicative of areas of necrosis and Lac peaks are directly originated from processes resulting in anaerobic metabolism. mI can be a marker of astrocytic metabolism and can be seen elevated in certain pathologic processes (see Table 1 ).



Table 1

Metabolites evaluated with magnetic resonance spectroscopy in brain tumor imaging


















































































Metabolite Peak Configuration Resonance (ppm) Best Echo Time for Detection Clinical Associations
NAA Singlet 2.0 Short or long TE Neuronal marker (not seen in non-neural brain tumors)
Cho Singlet 3.22 Short or long TE Membrane turnover marker and cellular proliferation
Cr Singlets 3.03 and 3.9 Short or long TE Cellular energy byproduct. Lower in necrosis
mI Multiplets 3.56 Short TE Low-grade gliomas, gliomatosis
Lip Broad peaks 0.9, 1.3 Short TE Tuberculomas, PCNSL, radiation necrosis
Lac Doublet 1.33 1.5T = inverted at 135–144 ms
3T = 288 ms
Anaerobic metabolism marker Prominent if necrosis or hypoxia
Glx Multiplets 2.1–2.4 ppm; 3.7 ppm Short TE Detected in GBM, astrocytomas and oligodendrogliomas
Taurine Triplets 3.4 Short TE Medulloblastomas
Alanine Doublet 1.47 1.5 T = 144 ms Meningiomas
Citrate Multiplets 2.6 3T = 35 ms and inverts at 97 ms Gliomas, particularly aggressive pediatric types
Gly Singlet 3.55 3T = 160 ms Low-grade gliomas, central neurocytomas
2HG Multiplets 1.85, 2.01, 2.28, and 4.05 Best seen with spectral editing techniques
3T = 97 ms
IDH mutations

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Sep 18, 2017 | Posted by in MAGNETIC RESONANCE IMAGING | Comments Off on Multiparametric Imaging Analysis
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