Magnetic resonance spectroscopy (MRS), like magnetic resonance imaging (MRI), is based on the principle of nuclear magnetic resonance (NMR). The technique of spectroscopy has been widely applied in chemistry for the analysis of compounds in solution. Although MRS can theoretically be performed in almost any tissue of the human body, the brain has been the major organ of interest for clinical MRS studies. This is due to the rather homogeneous tissue structure of the brain, its easy accessibility to MRS, and limited motion artifacts. MRS provides a non-invasive diagnostic tool for the biochemical characterization of pathophysiological processes in the brain. MRS of the brain parenchyma (neurospectroscopy) is of interest to physicians treating primary brain diseases and may also contribute to the diagnostic work-up of systemic diseases involving the central nervous system.
MRS TECHNIQUE AND OTHER CONSIDERATIONS
Clinical MRS became feasible with the development of a rapid, inexpensive, and automated technique that could be easily integrated with the MRI exam. As a clinical tool, MRS received approval of the United States Food and Drug Administration in 1995 (1). Though MRS can be performed using a variety of nuclei such as carbon (13C), nitrogen (15N), fluorine (19F), and sodium (23Na), only the nuclei phosphorus (31P) and hydrogen (1H) exist in vivo in concentrations high enough for routine clinical evaluation. Proton (1H) MRS studies have become popular due to the high natural abundance of protons and their high absolute sensitivity to magnetic manipulation, better spatial resolution, and relative simplicity of technique, as well as a shift of interest to areas of metabolism that lack phosphorylated metabolites (2-5).
MRS is performed in a fashion similar to MRI with the addition of a few steps before the data acquisition, a change not discernible to the patient undergoing the examination (1).
The first step used to obtain diagnostic data is ensuring the homogeneity of the magnetic field (1). This is accomplished by “shimming,” an automated process that on occasion may have to be performed manually (2,6).
The concentration of water exceeds the concentration of metabolites of interest by a factor of 10,000 or more. This means that the dominant resonance (the resonance peak) in a hydrogen spectrum will represent protons from the water molecule, dwarfing the millimolar concentrations of other metabolites (1,2,4,6). Hence, suppression of the water signal becomes a necessary step in MRS, achieved by the addition of water suppression pulses (1,6).
Commonly used spectroscopic techniques include the single voxel spectroscopy (SVS), with a spatial resolution in the order of one to eight cm3 (2), and the multi voxel technique, also called “chemical shift imaging” (CSI) or magnetic resonance spectroscopic imaging (MRSI), allowing the derivation of metabolite maps (7,8). The term “voxel” used here refers to the volume of tissue being investigated. Although SVS allows evaluation of only small volumes of tissue, it is time-efficient and allows the acquisition of quantitative data. CSI allows examination of a larger volume of tissue, which can then be evaluated using multiple smaller voxels (as small as one cm3) within the investigated volume (1,2,4,6,7,9). The two-dimensional CSI (2D-CSI or MRSI) technique requires longer acquisition and post-processing times. Recently, techniques for 3D MRSI have been developed (including 3D phase encoding CSI or multisection CSI) that allow spectral maps and metabolite images to be obtained from a large volume of the brain (10).
The selection of appropriate MRS techniques, including measurement parameters such as repetition time (TR) and echo time (TE), depends on the clinical question. Short TE (20 to 35 ms) evaluations are required when there is need for detection of metabolites with short relaxation times, such as glutamine, glutamate, myo-inositol, and certain amino acids (1,4,11,12). Long TE studies (135 to 270 msec) are sufficient for the detection of the major metabolites such as N-acetyl aspartate (NAA), choline (Cho), creatine (Cr), and lactate/lipids (LL) (4,6,12,13). The clinical question to be answered must therefore be determined before designing an MRS study.
There are several limitations to MRS regardless of the technique used. It is difficult to perform MRS in or adjacent to tissue with high differences in magnetic susceptibility compared with brain tissue, such as bone, air, fat, and hemorrhage. This is due to the artifacts arising from these structures and the resultant difficulty in obtaining a homogeneous magnetic field, essential for a good MRS study. Hence, spectra of good quality are difficult to obtain near the skull base, calvarial bone, paranasal sinuses, and mastoid air cells. The artifacts can contribute to so much spectral broadening that the spectra obtained from these regions may contain no discernible metabolite resonances, often rendering them useless. In particular, posterior fossa lesions and supratentorial lesions that lie in close proximity to the ventricular system or calvarial bone are considered difficult to evaluate with 2D-CSI. As a result, characterization of lesions in these challenging areas has generally relied on SVS, which is less prone to susceptibility artifacts. Recent studies (14,15) using 2D-CSI MRS have demonstrated that it may be possible to overcome this problem by using outer volume suppression slices and in-field-of-view saturation bands for the suppression of osseous structures, fat in the scalp, and air adjacent to the lesion of interest.
The amplitude of the metabolite resonances (peaks) differs depending on the TE, the TR, and the localization sequence. SVS automatically generates values for the signal intensity for a few of the metabolite resonances. In contrast, when 2D-CSI MRS is performed, further post processing is required to obtain the signal intensity values, quantify the metabolite concentrations, and calculate the various metabolite ratios. These calculations can be performed manually or by using automated calculation programs such as the linear combination model method (LC-model) (16) or Magnetic Resonance User Interface (MRUI) (17).
MAJOR METABOLITES AND THEIR SIGNIFICANCE
The results of MRS are displayed as a spectrum of resonances (peaks) distributed along the x-axis, labeled in parts per million (ppm). The amplitude of the resonances is measured on the y-axis using an arbitrary scale. In brain MRS, the resonances of interest are N-acetyl aspartate (NAA), choline (Cho), creatine (Cr), myo-inositol (mI), lactate (Lac), lipids (Lip), glutamine and glutamate (Glx), and amino acids (1-4,6,9,12) (Fig. 1) (Table 1).
N-acetyl aspartate (NAA) is the most prominent resonance (peak) with its major resonance at 2.02 ppm. NAA is considered a marker for neuronal and axonal integrity, although its exact physiologic role is unclear. A decrease in NAA levels is a sign of neuronal loss or damage and occurs with many types of insults to the brain (1,2,6,8,11,12). A physiologic gradual and progressive increase in NAA is seen during brain development and maturation in infancy (1).
Choline (Cho) is seen as a peak at 3.2 ppm and represents the sum of choline-containing compounds such as glycerophosphocholine, phosphatidylcholine, and phosphocholine (2,6). Cho therefore represents the constituents of the cell membrane and is a marker for membrane turnover (1,2,4,6,7,12). Increased Cho is seen in conditions with increased numbers of cells, increased membrane synthesis, or increased membrane breakdown (1,6,7,12), as in demyelination and malignant tumors.
Creatine (Cr), including phosphocreatine (PCr), is displayed at 3.0 ppm and is a marker for brain energy metabolism (1,2,4,6,7). It is fairly stable and commonly used as an internal standard (1,2,6,7). However, variations in Cr levels do occur, as in the gradual loss of Cr together with other major metabolites in tissue death or necrosis. Cr may increase as a hyperosmolar response to craniocerebral trauma, or be absent as in the case of creatine deficiency, a rare congenital disease (1,12).
Lactate (Lac) is seen as a doublet (twin peaks) at 1.33 ppm. In the normal human brain, lactate is at or below the level of detectability in most MRS studies, except perhaps in the CSF of normal subjects with enlarged ventricles (8). The presence of lactate usually signifies the interruption of oxidative phosphorylation, and initiation of anaerobic glycolysis (1,2,4,6,7) . Increased lactate is seen in hypoxia, ischemia, mitochondrial disorders, and some tumors (1,2,6,7,11,12). The lactate peak is upright (above the baseline) when the TE is low (20 to 35 ms) or high (270 to 288 ms). At an intermediate TE (135 to 144 ms), the lactate peak inverts to project below the baseline, a feature that allows its distinction from lipids and some macromolecules seen at a similar location on the spectrum (Fig. 2). This phenomenon of an inverting resonance at intermediate TE is also seen for the amino acid alanine (6).
Lipids are seen in the range between 0.9 and 1.5 ppm (1,11). An increase in lipids is seen in necrotic areas of tumors (6,8). The region of interest needs to be carefully located so as to avoid contamination from fat in the subcutaneous scalp or the skull base (2,6,11,18).
Myo-inositol (mI) is an osmolyte and astrocyte marker. Its resonance at 3.56 ppm is visualized when performing MRS using a short TE (1,2). An increase in mI has been seen, along with other findings, in Alzheimer's disease, frontotemporal dementia, and HIV infection (4).
Glutamine and Glutamate
Glutamine and glutamate are seen as multiple resonances between 2.2 and 2.4 ppm when using a short TE. Elevated levels of glutamine and glutamate have been reported in hyperammonemia secondary to hepatic encephalopathy and in other metabolic conditions resulting in hyperammonemia (3,11,19).
NORMAL VARIATIONS IN METABOLITE CONCENTRATIONS
There are age-related and regional variations in the concentrations of various metabolites in the brain. The age-related variations are more noticeable in the first years of life and mainly reflect myelination (1,4,6,7,20). The most striking change is an increase in the NAA/Cr ratio which peaks at 10-14 years, being higher in children than in normal adults and then reducing in the elderly (1). Regional variations of metabolite concentrations in the brain are seen between gray and white matter (NAA is higher in white matter and Cr and Cho are higher in gray matter) (1,21) and between the different parts of the brain (cerebrum and cerebellum, frontal and occipital lobes) (22).
CLINICAL APPLICATIONS OF MRS
Although MR spectra can be read visually, quantitative data and metabolite ratios are required for a precise interpretation (23-26). MRS spectra should always be read in conjunction with the morphologic information derived from imaging studies because many pathologic entities easily diagnosed with MRI or CT studies may be impossible to differentiate by MRS alone (2). Moreover, age and concentration differences for the observed metabolites throughout the brain must be factored in (11,12,23).
Brain neoplasms can be adequately evaluated using the MRSI technique. MRSI allows the inclusion of surrounding normal brain which may yield information related to the extent of the lesion and infiltration into surrounding parenchyma that appears normal on MRI (8,9,27).
In astrocytomas, MRS demonstrates an increase in Cho, reflecting a high cellularity and/or cell turnover (2,9,28). NAA is reduced since the normal neurons are replaced or destroyed by the mass (2,7) (Figs. 3, 4). Lactate may be present due to high glycolytic rates and also lipids due to cellular breakdown and necrosis (6,29). Some authors have suggested that in astrocytomas, decreasing NAA and increasing Cho and Cho/Cr ratios correlate with a higher WHO tumor grade (30,31), but this has not been consistently reported.
MRSI allows for evaluation of heterogeneous lesions with areas of proliferating tumor and necrosis, cysts, hemorrhage or edema, and adjacent normal-appearing brain tissue (9). Proton MRS cannot supplant biopsy but may be of help in guiding brain biopsy (27,32).
Previous studies utilizing MRSI have suggested that it is possible to separate infiltrative tumors from circumscribed lesions such as metastases. Infiltrative processes such as high grade astrocytomas demonstrate abnormal NAA/Cho ratios not only in the contrast-enhancing portions of the tumor, but also in the surrounding brain tissue, perhaps a sign of tumor infiltration (9) (Fig. 4). In contrast, metastases and other circumscribed lesions such as abscesses (33) or meningiomas (34) do not show severely abnormal NAA/Cho ratios outside the lesion (Fig. 5). The area of vasogenic edema surrounding focal lesions may yield a decrease in NAA/Cho ratio but without a significant increase in Cho/Cr. The area adjacent to an encapsulated abscess may show increased lactate and decreased NAA.
Extra-axial tumors, such as meningiomas and metastases, usually displace neuronal tissue and hence show very low levels or absence of NAA (2,6,9,30). Some NAA may be seen on the spectra due to inclusion of adjacent normal brain tissue in the volume of interest being sampled, a partial volume effect. This phenomenon is common when using SVS in small lesions or near the margins of a lesion in MRSI. Like other tumors, meningiomas and metastases show increased Cho levels (30). Meningiomas may show the presence of alanine (35-37). A reported case (38) has shown an elevated resonance at 2.05 ppm of an unidentified compound, which is not NAA, in a cystic metastasis from mucinous adenocarcinoma (Fig. 5).
New contrast-enhancing lesions that appear at the site of a previously identified and treated primary intracranial neoplasm present a significant diagnostic dilemma. MRS may be useful in the differentiation of tumor recurrence from radiation necrosis (31,39). Radiation changes include decreased NAA, Cho, and Cr resonances compared with normal brain tissue. Radiation necrosis may also show a broad resonance between 0 to 2 ppm, reflecting cellular debris containing lipids, lactate, and amino acids (6). However, coexistent viable tumor and radiation necrosis may be difficult to differentiate. 2D-CSI spectroscopy has been shown to be able to differentiate recurrent tumor from radiation injury, demonstrating significantly higher Cho/NAA and Cho/Cr ratios in recurrent tumor compared with radiation injury and normal-appearing white matter (39). A recent study utilizing MRS in posterior fossa tumors demonstrated significantly elevated Cho/Cr and Cho/NAA ratios in recurrent tumors following chemotherapy or radiation (15).
In a study evaluating patients with lung cancer who had received whole brain radiation therapy, MRS detected a decline in the whole brain NAA even when MMSE scores were unchanged, suggesting that MRS may be a more sensitive measure of radiation injury (40).
Acute multiple sclerosis (MS) lesions show an initial reduction in NAA which has been shown to recover partly over time. Contrast-enhancing lesions also are likely to show increased Cho and lipids, which are myelin breakdown products (2,41). Chronic MS lesions show reduced NAA, particularly in T1 hypointense lesions (42), which may also show increased myo-inositol, possibly indicating gliosis (41).
MRS studies have revealed spectral changes in gray matter, even though cortical lesions are seldom observed on MRI (41). More significantly, recent MRS studies indicate that normal-appearing white matter on MRI may display regional increases in choline and lipids (41,43). Reduction in NAA in the normal-appearing white matter may provide a better correlation with functional impairment than the number of T2 hyperintense lesions (44). Thus, MRS may be used for detection of axonal damage and demyelination in MS, and together with MRI and diffusion tensor imaging (DTI) (45), may provide a powerful measure to monitor MS evolution (46).
Systemic Lupus Erythematosus
Neuropsychiatric systemic lupus erythematosus (NP-SLE) occurs in 25-70% of patients with lupus and is associated with increased morbidity and mortality (47). The clinical manifestations of NP-SLE include psychosis, stroke, and epilepsy, in addition to more subtle symptoms such as headache and neurocognitive dysfunction (48). NP-SLE may present with seizures, movement disorders, altered consciousness, stroke, and coma (49). Some previous studies, mainly using single-voxel spectroscopy (SVS), have demonstrated a decrease in NAA/Cr and an increase in Cho/Cr in the white matter and basal ganglia of NP-SLE patients as compared with those of normal healthy volunteers (50-53).
In a study of acute NP-SLE patients (54), 2D-CSI MRS demonstrated significantly lower NAA/Cho, and significantly increased Cho/Cr and LL/Cr ratios as compared with normal volunteers. Further decrease in NAA/Cho and NAA/Cr ratios at a three month follow-up visit supported the assumption that neuronal damage, seen as a decline in NAA, might be irreversible even if the SLE patient receives appropriate treatment (54).
Acute Disseminated Encephalomyelitis (ADEM)
In a case report, increased lactate was detected in lesions of acute disseminated encephalomyelitis (ADEM) (55). Low levels of NAA on initial MRS were reported in a case of ADEM with multiple transient brain lesions on MRI (56). At final follow-up, neurologic examination and brain MRI findings and NAA levels had all recovered to normal. In contrast to other demyelinating diseases such as MS or leukodystrophy, choline levels were normal.
Spectroscopic abnormalities have been observed in neurologically normal HIV patients or those with normal MRI results (57-59). Increases in choline and myo-inositol are seen in virtually all cases of HIV infection (59,60), even in the early asymptomatic cases (61). Neurologically asymptomatic HIV patients have minimal or no change in NAA or NAA/Cr (58,61), but HIV dementia is associated with a decrease of NAA and NAA/Cr, especially in those with severe dementia (61). NAA can be used as a non-invasive measure of neuronal loss in patients with HIV disease (62).
Progressive Multifocal Leukoencephalopathy (PML)
Increased Cho/Cr and mI/Cr, and reduced NAA/Cr can be seen in progressive multi-focal leukoencephalopathy (PML) (1). This, however, is a non-specific finding as such a pattern of abnormal metabolic ratios may be seen in other diseases.
Toxoplasmosis vs Primary CNS Lymphoma
A lipid/lactate resonance and absence of other metabolites is seen in toxoplasmosis. A similar increase in lipid and lactate to that seen in toxoplasmosis may also be seen in necrotic portions of lymphoma and other tumors, but solid tumor in lymphoma shows increased Cho levels (1,60,63). However, there is an overlap between the spectral patterns of toxoplasmosis and primary CNS lymphoma (60,64).
Another use of proton MRS is in the non-invasive differentiation of brain abscess from other cystic lesions such as necrotic tumors. MRS may show an absence of normal metabolites in the central cystic portion of a medically untreated abscess, with resonances corresponding to acetate (1.9 ppm), lactate (1.3 ppm), pyruvate, and succinate (2.4 ppm) (end products of microbial metabolism), amino acids such as valine, leucine, and isoleucine (0.9 ppm) (end products of the action of proteolytic enzymes), alanine (1.5 ppm), and lipids (0.9-1.3 ppm) (8,33) (Fig. 6).
The use of proton MRS in the evaluation of metabolic disease in children is widely documented (11,12,65-78). Although 2D CSI can be used in many disease conditions, traditionally SVS has been the more commonly used technique in the evaluation of metabolic disorders. A full description of all entities is beyond the scope of this review and only the more common diseases are discussed here.
Mitochondrial disorders, including Leigh disease, Kearns-Sayre syndrome, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), and myoclonic epilepsy with ragged red fibers (MERRF) (11,12) share the metabolic consequence of a disruption of oxidative phosphorylation (cellular respiration). This results in anaerobic glycolysis and the accumulation of lactate in the brain (Fig. 7). MRS can demonstrate the presence of lactate (65,66) in normal-appearing brain tissue (67).
Peroxisomal disorders include the various forms of X-linked adrenoleukodystrophy (x-linked ALD), neonatal ALD, and Zellweger syndrome. In x-linked ALD, the MRS findings of reduction in the concentrations of NAA and glutamate (Glx) are consistent with neuronal damage or loss, and increased Cho levels indicate active demyelination (68). MRS has a special role in the management of patients with childhood ALD. Bone marrow transplant (BMT) is performed only on children with early CNS involvement, as patients with advanced disease fare poorly with this procedure (12,69). The detection of MRS abnormalities before the onset of neurologic symptoms may therefore help in the selection of patients (68). Serial MRS has been proposed to screen the population at risk for detection of the earliest signs of demyelination.
Lysosomal disorders include conditions such as metachromatic leukodystrophy, Krabbe disease, Niemann-Pick disease and mucopolysaccharidosis. In Krabbe disease, a markedly reduced NAA and an abnormally high Cho/ NAA ratio has been described in a case report (70). Metachromatic leukodystrophy is characterized by an increase in mI and lactate and a decrease in NAA (71).
Amino acid disorders. MRS changes have been reported in many of these conditions as case reports (72-75).
In phenylketonuria, increased levels of phenylalanine are observed in the blood with increased urine levels of phenylpyruvate. Central nervous system manifestations include mental retardation, spastic paraplegia, choreoathetosis and seizures. High T2 signal white matter changes seen on MRI have been shown to regress with dietary therapy (72). Resonances corresponding to phenylalanine have been demonstrated using short TE (73) at 7.37 ppm, in the spectral range far to the left of the other commonly evaluated metabolites. Other metabolites are usually normal (11,12).
In maple syrup urine disease, branched chain amino acids such as leucine, isoleucine, and valine are elevated, and a corresponding resonance is seen at 0.9 ppm (7,11,12,73). MRS has been shown to be positive even when MRI is negative, and the resonance decreases with successful treatment (12).
Canavan disease is a disorder with a congenital defect in the metabolism of NAA involving the enzyme aspartoacylase. This results in an increase in NAA levels in the brain (76,77). Low Cho levels have also been reported (76). MRS may be diagnostic in such children presenting with macrocephaly. Alexander disease shows a reduced NAA and increased lactate (78).
MRI with diffusion weighting is the technique of choice in the evaluation of acute ischemic stroke (7). MRS changes include a decrease in NAA that occurs over several days after the stroke. NAA may pseudonormalize several weeks after the event due to brain atrophy. Lactate rises early after the insult in the acute phase (<24 hours) and may remain high over a long period into the chronic phase (>7 days) (2,6,8).
In cases of global hypoxic-ischemic insults, NAA and lactate levels in gray matter may have prognostic significance (8). In two studies (79,80), high lactate and lipids and low NAA were found in newborns with the worst outcome.
Temporal lobe epilepsy (TLE) is typically evaluated with high resolution MRI studies, which often show hippocampal or mesial temporal sclerosis. In many cases, however, MRI findings may be subtle or inconclusive (6,7). TLE can also be studied by MRS (3,81,82), which has shown reduced NAA representing neuronal loss or dysfunction (2). Lactate may increase in a seizure focus, persist for several hours, and be used as a marker for seizure activity (2,7,11). In the post-ictal period, the presence of lactate is helpful in lateralizing seizure activity (83).
Neurodegenerative disorders are a diverse set of conditions with varied etiologies. Patients with Alzheimer disease show reduced levels of NAA along with a significant increase in myo-inositol (2,4,6,7). Similar changes may be seen in frontotemporal dementia but in a different distribution (4,7). Findings in multi-infarct dementia are non-specific with low levels of NAA; in severe cases, lactate may be present, or myo-inositol may be increased indicating gliosis (4).
Traumatic Brain Injury
MRS has demonstrated a reduction in NAA, a reflection of diffuse axonal injury or metabolic depression. Concentrations of NAA predict cognitive outcome (84). An initial fall and subsequent recovery of NAA in white matter has been noted, suggesting a reversible metabolic derangement. In contrast, NAA concentration in gray matter was found to fall continuously after trauma (85). Elevation of Cho is also noted early after the injury, suggesting an inflammatory response. The elevation in Cho in the gray matter was seen to persist, possibly reflecting ongoing inflammation (85).
In adults, MRS studies have demonstrated metabolic changes in normal-appearing white matter and a correlation between NAA/Cr ratio and severity of head injury (86,87). Similar findings have been seen in neonates and children with significantly lower NAA/Cr ratios in those with poor outcome (88). NAA concentrations can evidently predict long-term neurologic outcome (88). However, a recent case report found an almost complete recovery in NAA in a patient with diffuse axonal injury (89).
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