Magnetic resonance spectroscopy is a non-invasive technique that can be used to measure the concentrations of different low-molecular weight chemicals. It differs from conventional Magnetic Resonance Imaging in that spectra provide physiological and chemical information instead of anatomy. The high diagnostic specificity of MRS enables the biochemical changes that accompany various neurological disorders to be detected, as well as disease characterization, sometimes diagnosis, and monitoring. In this paper we discuss the physical basis, normal spectra, clinical applications and results interpretation of MRS in the evaluation of neurological disorder.
Keywords: magnetic resonance spectroscopy, neurological disorder
Magnetic resonance spectroscopy of the brain reveals specific biochemical information about cerebral metabolites and function of the normal and pathological structures of the brain. (1, 2)
MRS produces a spectra of resonances correspondent to a series of metabolites, in a
system of two axes, which represent the intensity of the signal (vertical axis) and the position of the signal in the frequency scale (horizontal axis, respectively), expressed in parts per million (ppm)The spectrum is measured within a volume of interest (VOI), which is defined on the morphological multiplanar sequences previously acquired during the examination.(3)
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Brain MRS has a number of clinical applications, including the characterization of cerebral tumors and the monitoring of their treatment (e.g., radiation necrosis versus recurrence tumor), epilepsy, infection, stroke, multiple sclerosis (MS), trauma, neurodegenerative processes, such as Alzheimer's and Parkinson's diseases (4), and allows to diagnose several hereditary and acquired brain metabolic disorders such as Canavan's disease (5), brain creatine deficiency syndromes (6), adrenoleukodystrophy and hepatic encephalopathy (7)
The resonant frequencies (RF) of protons range between about 10 MHz at 0.3 T to about 300 MHz on a 7 T magnet. The advantages of higher field strength are higher signal-to-noise and better separation of the metabolite peaks. In a proton spectrum at 1.5 T, the metabolites are spread out between 63,000,000 and 64,000,000 Hertz. Some physicians decided to express the resonant frequencies in parts per million (ppm), and they positioned NAA at 2.0 ppm and let the other metabolites fall into their proper positions on the spectral line. Then reversed the ppm scale so that it reads from right to left.
Each metabolite appears at a specific ppm, and each one reflects specific cellular and biochemical processes. The observable MR metabolites provide powerful information, but unfortunately, many notable metabolites are not represented in brain MR spectra such as DNA, RNA, most proteins, enzymes, and phospholipids. Some neurotransmitters, such as acetylcholine, dopamine, and serotonin, are absent. Either their concentrations are too low, or the molecules are invisible to MRS.
The predominant metabolites, displayed from right to left, are NAA, creatine, choline, and myo-inositol. Hunter's angle is the line formed by the metabolites on the white matter spectrum (figure1). The common way to analyze clinical spectra is to look at metabolite ratios, namely NAA/Cr, NAA/Cho, and Cho/Cr (table 1and 2). (8)
1: N-acetylaspartate (NAA):
Peak of NAA is the highest peak in normal brain. This peak is assigned at 2.02 ppm. NAA is synthesized in the mitochondria of neurons then transported into neuronal cytoplasm and along axons. NAA is exclusively found in the nervous system.It is a marker of neuronal and axonal viability and density. NAA also plays a role as a cerebral osmolyte. Absence or decreased concentration of NAA is a sign of neuronal loss or degradation. Neuronal destruction from malignant neoplasms and many white matter diseases result in decreased concentration of NAA. Increased NAA is nearly specific for Canavan disease. NAA is not demonstrated in extra-axial lesions such as meningiomas or intra-axial ones originating from outside of the brain such as metastases.
2: Creatine (Cr):
The peak of Cr spectrum is assigned at 3.02 ppm. This peak represents a combination of molecules containing creatine and phosphocreatine. Cr is a marker of energetic systems and intracellular metabolism. Concentration of Cr is relatively constant and it is considered a most stable cerebral metabolite. Therefore it is used as an internal reference for calculating metabolite ratios.
In brain tumors, there is a reduced Cr signal. Gliosis may cause minimally increased Cr due to increased density of glial cells (glial proliferation). Creatine and phosphocreatine are metabolized to creatinine that excreted via kidneys. Systemic disease (e.g. renal disease) may also affect Cr levels in the brain.
3: Choline (Cho):
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Its peak is assigned at 3.22 ppm and represents the sum of choline and choline-containing compounds (e.g. phosphocholine). Cho is a marker of cellular membrane turnover (phospholipids synthesis and degradation) reflecting cellular proliferation. In tumors, Cho levels correlate with degree of malignancy reflecting of cellularity. Increase Cho may be seen in infarction (from gliosis or ischemic damage to myelin) or inflammation (glial proliferation) hence elevated Cho is nonspecific.
4: Lactate (Lac):
Peak of Lac is not seen or is hardly visualized in the normal brain. The peak of Lac is a doublet at 1.33 ppm. A small peak of Lac can be visible in some physiological states such as newborn brains during the first hours of life. Lac is a product of anaerobic glycolysis so its concentration increases under anaerobic metabolism such as cerebral hypoxia, ischemia, seizures and metabolic disorders (especially mitochondrial ones). Increased Lac also occur with macrophage accumulation (e.g. acute inflammation). Lac also accumulates in tissues with poor washout such as cysts, normal pressure hydrocephalus, and necrotic and cystic tumors.
5: Lipids (Lip):
Lipids are components of cell membranes. Presence of lipids may result from improper voxel selection causing voxel contamination from adjacent fatty tissues (e.g. fat in subcutaneous tissue, scalp and diploic space). Lipid can be seen when there is cellular membrane breakdown or necrosis such as in metastases or primary malignant tumors.
6: Myoinositol (Myo):
Myo is a simple sugar assigned at 3.56 ppm. Myo is considered a glial marker because it is primarily synthesized in glial cells, almost only in astrocytes. It is also the most important osmolyte in astrocytes. Myo may represent a product of myelin degradation. Elevated Myo occurs with proliferation of glial cells or with increased glial-cell size as found in inflammation. Myo is elevated in gliosis, astrocytosis and in Alzheimer's disease.
7: Alanine (Ala):
Ala is an amino acid that has a doublet centered at 1.48 ppm. Increased concentration of Ala may occur in oxidative metabolism defects. In tumors, elevated level of Ala is specific for meningiomas.
8: Glutamate-Glutamine (Glx):
Glx is a complex peaks from glutamate (Glu), Glutamine (Gln) and gamma-aminobutyric acid (GABA) assigned at 2.05-2.50 ppm. These metabolite peaks are difficult to separate at 1.5 T. Elevated concentration of Gln is found in a few diseases such as hepatic encephalopathy .(9)
Main clinical applications:
1: Brain masses:
The evaluation of brain masses-most importantly, intraaxial masses-is the most common clinical application of MRS.
It plays an important role to differentiate a neoplasm from mimics such as multiple sclerosis and subacute ischemic infarction. MRS can also help to grade tumors and to distinguish primary CNS neoplasms from metastasis. The final major application of MRS is differentiating of radiation necrosis from recurrent tumor. (10)
MRS can be used to determine the degree of malignancy. As a general rule, as malignancy increases, NAA and creatine decrease, and choline, lactate, and lipids increase. NAA decreases as tumor growth displaces or destroys neurons.Very malig-nant tumors have high metabolic activity and deplete the energy stores, resulting in reduced creatine (figure 2). Very hypercellular tumors with rapid growth elevate the choline levels. Lipids are found in necrotic portions of tumors, and lactate appears when tumors outgrow their blood supply and start utilizing anaerobic glycolysis. Multi-voxel spectroscopy is best to detect infiltration of malignant cells beyond the enhancing margins of tumors. Particularly in the case of cerebral glioma, elevated choline levels are frequently detected in edematous regions of the brain outside the enhancing mass. Finally, MRS can direct the surgeon to the most metabolically active part of the tumor for biopsy to obtain accurate grading of the malignancy.
A common clinical problem is distinguishing tumor recurrence from radiation necrosis. Elevated choline is a marker for recurrent tumor. Radiation change generally exhibits low NAA, creatine, and choline on spectroscopy. If radiation necrosis is present, the spectrum may reveal elevated lipids and lactate. .(8,10)
2: Cerebral ischemia and infarction:
When the brain becomes ischemic, it switches to anaerobic glycolysis and lactate accumulates.Markedly elevated lactate is the key spectroscopic feature of cerebral hypoxia and ischemia. Choline is elevated, and NAA and creatine are reduced.If cerebral infarction ensues, lipids increase.(8)
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MRS is not routinely used in the acute setting of head injuries. CT and MR imaging demonstrate the fractures and intracranial hemorrhage that require emergent surgical intervention. When the patient has stabilized, MRS is helpful to assess the degree of neuronal injury and predict patient outcomes. Especially in the case of diffuse axonal injury; imaging often underestimates the degree of brain damage. Clinical outcome correlates inversely with the NAA/Cr ratio. The presence of any lactate or lipid indicates a worse prognosis.(8)
4: Infectious diseases:
Brain abscesses destroy or displace brain tissue, so NAA is not present. Lactate, cytosolic acid, alanine, and acetate are characteristic metabolites in bacterial abscesses. Toxoplasmosis is characterized by markedly increased lactate and lipids and depletion of normal brain metabolites. Tuberculoma and cryptococcoma are similar but with relatively little lactate.
When patients with AIDS start developing neurocognitive deficits and AIDS dementia complex, the MR spectra become positive with elevated choline and reduced NAA. Choline is the best marker for the white matter abnormalities, and the extent of NAA depletion correlates directly with the degree of dementia. MRS is also very helpful in following patients and assessing the effects of anti-viral therapies.
In common focal brain lesions in AIDS patients, the most helpful marker is choline, which is elevated in lymphoma, but low or absent in toxoplasmosis, tuberuloma, and cryptococcoma. The spectrum for PML may be similar to lymphoma, but the imaging features are distinctly different and PML may have elevated myo-inositol.(8)
5: Multiple sclerosis:
MS is the most common demyelinating lesion. MRS changes that occur during the development of an acute MS plaque include elevation of Cho and a decline in NAA .(13)After the acute phase these metabolic changes can return to normal. However, MRS of a chronic plaque may reveal a permanent decline in the NAA along with a persistent elevation of the Cho. NAA in normal-appearing white matter may also be reduced in patients with longstanding multiple sclerosis. (13)
6: Pediatric metabolic disorders:
MRS has a very important role in diagnosing and monitoring of patients with metabolic disorders. Some of the more important diseases are listed below, along with their specific metabolic markers on MRS.
Compared to the adult, newborns have much less NAA, and increased choline and myo-inositol (table3).
Variations of Major 1H Magnetic Resonance Spectroscopy Metabolites in Selected Inborn Errors of Metabolism
Phenylalanine (7.3 ppm) ↑
Glycine (3.5 ppm) ↑
Maple syrup urine disease
Branched-chain amino acids and oxo-acids (0.9-1 ppm) ↑
Creatine deficiency, GAMT deficiency, AGAT deficiency
Absence of creatine
NAA ↓ / no NAA
7: Hepatic encephalopathy:
Hepatic encephalopathy is characterized by markedly reduced myo-inositol.Choline is also reduced, and glutamine is increased. Liver failure results in excess ammonia in the blood. Ammonia is a neurotoxin and causes increased conversion of glutamate to glutamine. Similar metabolic changes are seen in Reye's syndrome. The metabolic changes of hepatic encephalopathy increase after a TIPS shunt procedure, and they revert back to normal after successful liver transplantation. (8)
8: Alzheimer's disease:
As the Alzheimer's disease progresses, the spectrum becomes abnormal. Specifically, with advancing disease the NAA is reduced and myo-inositol becomes elevated.
Myo-inositol is also increased in Down's syndrome.On the other hand, myoinositol is not elevated in other adult dementia, so it is a helpful marker to distinguish Alzheimer's disease from the other causes of dementia (table4 and 5).(8)
Variations of Major 1H Magnetic Resonance Spectroscopy (MRS) Metabolites in Selected Psychiatric Disorders
Cr and Cho in children ↑
31P MRS: PME ↓ and PDE ↑
After treatment: NAA ↑
Major depressive disorder
After SSRI treatment GABA ↑
After Li treatment:
31P MRS: asymmetric PCr
Change in NAA, Cho Glu, MI and Cr
Posttraumatic stress disorder
NAA ↓ in adults and children
MRS should be performed as an adjunct to MRI gain additional information for a reliable clinical diagnosis: while conventional MRI provides anatomical images of the brain, MRS provides functional information related to its underlying dynamic physiology.