Brain Proton Magnetic Resonance Spectroscopy

Introduction

The first reported in vivo localized proton ( ¹ H) magnetic resonance spectroscopy (H1-MRS) studies of the human brain were first reported over 20 years ago. Since these early studies, in vivo H1-MRS brain studies have been shown to be a powerful technique to noninvasively investigate the biochemistry of the human brain and to assess in situ the neurochemical profile of brain tissue. Thus they can provide biomarkers of neurologic disorders even in cases where lesions are not seen in conventional anatomic MRIs. The noninvasive quality of H1-MRS and the spatially localized MR techniques that have been developed to examine in vivo the neurochemical profile of brain tissue makes them suitable not only for diagnostic purposes but also longitudinal follow-up studies. They have proven to be important tools at many institutions for the noninvasive clinical assessment of numerous neurologic disorders such as brain tumors, epilepsy, white matter disease processes, metabolic disorders, and brain trauma. However, even though proton MRS has been incorporated into clinical protocols and is accepted at many institutions worldwide, it is still considered an investigational technique by some healthcare organizations, who indicate that at the present time there has been “no large multicenter trial published demonstrating any added benefit of MRS over MRI in diagnosing or monitoring pathological processes such as brain tumors, and no clinical trials demonstrating improved outcomes evaluated with MRS alone compared to patients evaluated with conventional imaging modalities have been reported.” What is not understood by these healthcare organizations is that MRS and MRI are not competitive techniques but rather complementary techniques that can “add value” to the MR diagnostic procedure and lead to better patient management decisions. MRS provides information about the metabolic profiles of lesions, whereas conventional MRI provides anatomic profiles, and in most cases it should not be used alone in making clinical diagnostic decisions but used in conjunction with the clinical history of the patient and information from conventional anatomic and advanced MRI techniques. As an example, Moeller-Hartmann and coworkers examined the diagnostic benefits of adding MRS to a conventional anatomic MRI study of intracranial mass lesions (i.e., infarctions, primary brain tumors, metastatic lesions, primitive neuroectodermal tumors, abscesses). In this study they found that with conventional MRI alone, 96 out of 176 correct diagnoses were made (55.1%). Adding H1-MRS information to the MRI findings led to an increase in the number of correct diagnoses from 96 to 124 out of the 176 cases (a 15.4% increase in correct diagnoses). By adding MRS to the MRI study, the number of incorrect diagnoses decreased from 27 (15.3%) for MRI alone to 16 (9.1%). Similarly, in a 2012 study it was shown that H1-MRS added value to conventional MRI information in the preoperative characterization of the type and grade of brain tumors. This study found that information obtained from “H1-MRS significantly improved the radiologists' MRI based characterization of grade IV tumors (glioblastomas (GBs), metastases, medulloblastomas, and lymphomas) in the cohort” (area under the receiver operating curve [AUC] from 0.85 in the MRI [alone] to 0.93 in the MRI plus MRS reevaluation [MRI plus MRS] and also in the less malignant glial tumors [AUC in the MRI reevaluation was 0.93 versus 0.81 in the MRI alone]).

This chapter will not review the basic principles of MRS and in vivo H1-MRS/MRSI of the human brain. The fundamental principles of this technique have been presented in detail elsewhere. The main body of this chapter will concentrate on the complementary use of H1-MRS with advanced MRI techniques (i.e., diffusion-weighted imaging [DWI], perfusion-weighted imaging [PWI], and permeability), and conventional MRI to improve the accuracy of diagnosis and delineation of brain tumors and in therapeutic decision making. The major reason for this is because of the important findings and recommendations on the use of MRS recently published by the MR Spectroscopy Consensus Group. This group was formed in 2011 under the auspices of the International Society of Magnetic Resonance in Medicine and is composed of leading imaging scientists, neuroradiologists, neurologists, oncologists, and clinical neuroscientists from universities, as well as vendors from the United States, Europe, and Asia. This international group was charged with the task of documenting “the impact of H-1 MR spectroscopy in the clinical evaluation of the central nervous system.” One of the major conclusions and recommendations of this group was that “MR spectroscopy adds diagnostic and prognostic benefits to MR imaging and aids in treatment planning and monitoring of brain cancers,” and that “clinical imaging centers specializing in combined use of MR imaging and spectroscopy should be established in all major clinical neurologic centers that offer standardized MR spectroscopy procedures for improved patient management.” This conclusion was based on the substantial body of both basic science and clinical MRS research that has been performed over the past 2 decades worldwide, with consistent results found across laboratories. This chapter will demonstrate that MRS, especially if combined with advanced MRI techniques, (1) can improve the diagnostic accuracy identifying neoplastic from nonneoplastic brain processes, (2) can identify the presence or absence of specific metabolites in the ¹ H MR spectrum that can be used as biomarkers to identify various tumor processes, and (3) that the combination of conventional and advanced MRI and MRS can reduce the need for more invasive diagnostic procedures to assess the cellular characteristics of untreated and treated brain tumor processes.

The MR paradigms described in the brain tumor studies can serve as models for the potential development of combined MRS and MRI techniques to increase diagnostic accuracy and modify patient treatment planning to improve the therapeutic outcomes in other central system disorders presented in this chapter and in the MR Spectroscopy Consensus Group report.

MRI vs. MRS

There is no difference between the physical principals of MRI and MRS; both techniques are governed by the same principles of magnetism. MRI and MRS differ only in the manner in which the data obtained are analyzed and the type of information provided. In the case of MRI, data collected are analyzed in the time domain (namely, free induction decay signal; signal intensity vs. time) to obtain relaxation time (TR) information (namely, T1 [spin-lattice] and T2 [spin-spin]) of the nuclei. The data from the time domain information is then used to generate an anatomic image. In MRS, the time domain information is converted to the frequency domain (signal intensity vs. frequency) via Fourier transformation of the free induction decay time domain signal. The frequency information generated via Fourier transformation of the time domain signal is used to form a distribution of the intensities of chemical groups associated with various metabolites versus their Larmor resonance frequencies ( Fig. 17-1 ) to give a spectral profile of the metabolites within this region of the anatomic image. Thus the two MR techniques (i.e., conventional MRI vs. MRS) give different but complementary information about the region being examined. In the case of conventional MRI (namely, T1- and T2-weighted MRI), the information is mainly anatomic in nature, generated via water proton interactions with the tissues, whereas MRS gives information about the biochemical/metabolic profile of the anatomic region being examined. Advanced MRI techniques such as PWI and DWI give physiologic information about the vascularity and cellularity of the anatomic region being evaluated. This information is also complementary to the information obtained from conventional anatomic MRI studies and biochemical/metabolic MRS studies. The major advantage of employing MR techniques to assess a lesion is that these complementary diagnostic techniques are noninvasive and can be performed during the same examination session (normally < 1.5 hours) to obtain multiparametric diagnostic information.

Evaluation of Brain Metabolites

MRS Observable In Vivo Brain Metabolites

Several important metabolites are evaluated in long echo time (TE) (135-288 milliseconds) proton MR spectra ( Fig. 17-2 ):

• N -acetylaspartate (NAA)

• Choline (Cho)

• Creatine/phosphocreatine (Cr/PCr)

• Lactate (Lac)

When short TEs (20-30 milliseconds) are used, a greater number of metabolites can be identified in the MR spectra; in addition to NAA, Cho, Cr, and Lac, the following may be identified :

• Glutamate (Glu)

• Glutamine (Gln)

• γ-Aminobutyric acid (GABA)

• Myoinositol (MI)

• Alanine (Ala)

• Glucose (Gc)

• Lipids and proteins

• Scylloinositol/taurine

Although it may appear advantageous to obtain spectra routinely at only short TEs to distinguish among different clinical entities, some disadvantages of short TE studies exist. For example, short TE spectra display greater baseline distortion, and estimating signal areas calls for more sophisticated processing software algorithms. However, to maximize metabolite information, both a short and long TE MRS study should be performed.

N -Acetylaspartate.

NAA accounts for the majority of the NAA resonance at 2.01 ppm; this signal is the most prominent one in normal adult brain proton MRS and is used as a reference for determination of chemical shift. The NAA signal also contains contributions from other N -acetyl groups, such as N -acetylaspartyl glutamate (NAAG), N -acetylated glycoproteins, and amino acid residues in peptides. NAA is second only to Glu as the most abundant free amino acid in the normal adult brain. The function of this amino acid is not fully understood despite its early discovery in 1956 by Tallan.

From animal studies, NAA is believed to be involved in coenzyme A (CoA) interactions and in lipogenesis within the brain. Specifically, such studies suggest that NAA is synthesized in the mitochondria from aspartate and acetyl CoA and transported into the cytosol where it is converted by aspartoacylase into aspartate and acetate. Although NAA is widely regarded as a nonspecific neuronal marker, it has also been detected in immature oligodendrocytes and astrocyte progenitor cells.

Normal absolute concentrations of NAA in the adult brain are generally in the range of 8 to 9 mmol/kg, although regional and age-related variations in NAA concentration have been noted by Kreis and others. In normal adults, NAA concentrations in cortical gray matter are higher than those in white matter; in infants the concentrations in gray and white matter are similar (highly active lipid synthesis in immature white matter accounts for this difference from the adult pattern). NAA concentrations are decreased in many brain disorders, resulting in neuronal and/or axonal loss, such as in neurodegenerative diseases, stroke, brain tumors, epilepsy, and multiple sclerosis, but are increased in Canavan's disease.

Creatine.

The main Cr signal is present at 3.03 ppm and demonstrates major contributions from methyl protons of creatine and phosphocreatine as well as minor contributions from GABA, lysine, and glutathione. A second, usually smaller Cr signal is seen at 3.94 ppm. Cr is probably involved in maintenance of energy-dependent systems in brain cells by serving as a reserve for high-energy phosphates in neurons and as a buffer in cellular adenosine triphosphate/diphosphate (ATP-ADP) reservoirs. Thus the Cr signal is an indirect indicator of brain intracellular energy stores.

The Cr signal is often used as an internal reference standard for characterizing other metabolite signal intensities because it tends to be relatively constant in each tissue type in normal brain; however, this is not always true in abnormal brain tissue, particularly in areas of necrosis. Cr concentrations in the brain are relatively high, with progressive increases noted from white matter to gray matter to cerebellum. Kreis and coworkers noted a mean absolute Cr concentration in normal adult brains of 7.49 ± 0.12 mmol/kg on the basis of a sample of 10 normal subjects, whereas Michaelis and colleagues reported a similar value of 5.3 mmol/kg. Total Cr values tend to be abnormally reduced in brain tumors, particularly malignant ones.

Choline.

The Cho resonance is present at 3.2 ppm and is attributable to trimethyl ammonium residues of free Cho as well as phosphocholine, phosphatidylcholine, and glycerophosphocholine. This signal reflects cell membrane synthesis and degradation. Thus all processes resulting in hypercellularity (e.g., primary brain neoplasms or gliosis) or myelin breakdown (demyelinating diseases) lead to locally increased Cho concentration, whereas hypomyelinating diseases result in decreased Cho levels. Kreis and coworkers have reported a mean absolute Cho concentration in normal adult brain tissue of 1.32 ± 0.07 mmol/kg. Michaelis and others have reported a similar value of 1.6 mmol/kg.

Myoinositol.

MI produces two signals noted at 3.56 ppm and 4.06 ppm. MI is the major component of the signal at 3.56 ppm, although contributions from MI-monophosphate and glycine are also present. MI is believed to be a glial marker because it is present primarily in glial cells and is absent in neurons.

A role in osmotic regulation of the brain has been attributed to MI. In addition, MI may represent both a storage pool for membrane phosphoinositides involved in synaptic transmission and a precursor of glucuronic acid, which is involved in cellular detoxification. A derivative, MI-1,4,5-triphosphate, may act as a second messenger of intracellular calcium-mobilizing hormones.

The mean absolute concentration of MI in normal brain tissues obtained in the Kreis series was 6.56 ± 0.43 mmol/kg. MI concentrations are abnormally increased in patients with demyelinating diseases, Alzheimer's disease, and low-grade brain tumors.

Lactate.

Lac resonance is identified as a doublet (splitting into two distinct resonant signals separated by 7 Hz), produced by magnetic field interactions among adjacent protons (referred to as J-coupling ) centered at 1.32 ppm. A second Lac signal is present at 4.1 ppm but tends to be inconspicuous on spectra obtained with water suppression owing to its proximity to the water signal. Because Lac levels in normal brain tissue are absent or extremely low (<0.5 mmol/L), they are essentially undetectable on normal spectra. The presence of a visible Lac signal constitutes a nonspecific indicator of cellular anaerobic glycolysis, which may be seen with brain neoplasms, infarcts, hypoxia, metabolic disorders, or seizures. Lac may also accumulate within cysts or foci of necrosis.

Changing the TE using a point-resolved spectroscopy (PRESS) sequence enables confirmation of the presence of an abnormal Lac doublet and differentiation from lipid signals; at TE = 20 and 272 milliseconds the Lac doublet projects above baseline, and at TE = 136 milliseconds it is inverted below the baseline. In encephalopathic neonates, however, a doublet very similar to Lac may be seen at 1.15 ppm, which corresponds to propan-1,2-diol and may easily be mistaken for Lac; propan-1,2-diol is a solvent commonly used for administration of anticonvulsant medications to neonates.

Glutamate, Glutamine, and GABA.

The glutamate and glutamine (“Glx”) and GABA signals are a complex set of resonances noted between 2.1 and 2.5 ppm and consist of Glu, Gln, and GABA components. Glu is an excitatory neurotransmitter involved in neuronal mitochondrial metabolism and is the most abundant amino acid in the human brain. Gln is involved in both cellular detoxification and regulation of neurotransmitter activities. GABA is a product of decarboxylation of Glu via glutamic acid decarboxylase and serves as an inhibitory neurotransmitter. Abnormalities in this signal complex have been noted in schizophrenia and epilepsy.

Lipids and Proteins.

Lipids produce multiple resonances, the most important of which are noted at 0.8 to 0.9 and 1.2 to 1.3 ppm because of methyl and methylene protons of fatty acids, respectively. Membrane lipids are not usually identified unless very short TEs are employed, because they have very short TRs and are not normally observed. Although artifactual accentuation of these signals may be seen with voxel contamination by adjacent subcutaneous fat, they can be eliminated by using outer volume suppression saturation pulses. High-grade gliomas (HGGs), meningiomas, demyelinating processes, necrotic foci, and inborn errors of metabolism can show the presence of lipids owing to the presence of lipid droplets within necrotic tumors, loosening of the lipid-rich myelin sheath, and breakdown of plasma membrane structures of cells.