Brain Spectra

What do the peaks seen in routine brain MRS represent?  

Three major ¹H spectral peaks are consistently identified in the normal brain at 1.5T and 3.0T: NAA (N-acetyl aspartate), Cr (creatine), and Cho (choline). When relatively short echo times are used, peaks for mI (myo-inositol) and Glx (glutamate/ glutamine) may be seen. Lac (lactate) is not present in the normal adult brain but may be identified in neonates. Broad peaks due to mobile lipids (Lip) and macromolecules (MM) are also a well recognized feature of spectra obtained at short TE values.  ​At very high fields (≥7.0T) and in certain diseases small additional peaks may be identified, described in the Advanced Discussion.

Normal brain ¹H spectrum at short TE (35 ms) shows characteristic peaks described below

A brief summary of the commonly seen major brain metabolites and their principal spectral peaks is provided below. Although each metabolite has several chemically distinct ¹H nuclei contributing to the spectrum, usually only one (or two) of these are large enough to be detected in clinical MR studies.  

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N-acetyl aspartate (NAA)

• Tallest peak in spectrum (δ = 2.0)
• Present primarily in neurons – a marker of neuronal density and viability
• Decreased in any disease that destroys neurons (stroke, MS, tumor, dementia, epilepsy)
• Metastatic and non-neural neoplasms (meningiomas) do not contain NAA
• Elevated in Canavan's disease

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Creatine (Cr)

• Two peaks (at δ = 3.0 and 3.9, corresponding to blue and red hydrogens, respectively)
• Peak includes both Creatine (Cr) and Phosphocreatine (PCr), involved in energy metabolism
• PCr + ADP ↔ ATP + Cr
• Produced in liver and transported to brain where its level is relatively constant; serves as internal standard
• Decreased in most brain diseases; absent in metastases

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Choline (Cho)

• 3rd tallest peak (δ = 3.2)
  
• Includes dominant contributions from phosphorylcholine and glycerophosphorylcholine; free Cho content is low in normal brain
• Major constituents of cell membranes 
• Elevated in diseases with high membrane turnover (ischemia, demyelination, tumors, inflammation)
• Especially elevated in malignancy, where Cho/Cr ratio may be inverted

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Myo-inositol (mI)

• Several multiplet peaks, largest near δ = 3.6; isomer scyllo-inositol (sI) is small singlet at 3.3 ppm
• Glucose-like metabolite found principally in astrocytes; regulates cellular volume
• Due to short T2, best seen on short TE studies
• Elevated in neonates, gliosis, acute demyelination, schwannomas, tuberous sclerosis, cortical dysplasias
• Decreased in any chronic process destroying astrocytes (ischemia, neoplasm, demyelination)

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Glutamate/Glutamine (Glx)
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Glutamate (Glu) is shown. For Glutamine (Gln) the left O⁻ is replaced by NH₂

• Glutamate (Glu) is the major excitatory neurotransmitter released by neurons
• Nearby astrocytes take up glutamate, converting it to glutamine (Gln) which is recycled to the neuron for reprocessing into glutamate
• Glutamate and glutamine resonate closely together, their summed peak called Glx and assigned to δ ≈ 2.3
• Increased in hepatic encephalopathy and many acute brain diseases (stroke, demyelination, epilepsy) 
  

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Lactate (Lac)

• Peak at δ = 1.3, characteristic doublet that is upright at TE = 30 and 288 ms, but inverted at TE = 144 ms
• Not present in normal brain (except neonates)
• Product of anaerobic metabolism
• Elevated in ischemia/infarction (hypoxia), in tumors (glycolysis and increased oxygen demand), and spectral "contamination" by CSF (which normally contains Lac)

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Lipids (Lip)

• Signals arise from mobile tissue triglycerides and free fatty acids 
• Two broad peaks at δ = 0.9 ppm (−CH3) and 1.3 ppm (−CH2−), best seen on short TE spectra
• Increased in wide range of destructive cellular processes (necrosis, inflammation, malignancy)
• Macrophages often contain high Lip concentrations

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Macromolecules (MM)

• At least 40 short but wide overlapping peaks, the largest in bands between δ = 0.9−2.2 and 3.7−4.2 ppm
• Due to very short T2 values seen only at short TE's and contribute undulation in spectral baseline
• Responsible metabolites not fully identified, but thought to arise from amino acid residues in >3500 Da proteins and polypeptides of brain cytosol
• MM peak elevated in any disease that injures brain cells

Advanced Discussion (show/hide)»

Less Commonly Observed Brain Specta

Acetate (Ac), the anion of acetic acid, commonly accumulates in bacterial abscesses due to enhanced glycolysis and fermentation by the infecting organism. It produces a singlet peak at 1.91 ppm. Acetate is also elevated in the in Canavan's disease due to deficiency of the enzyme aspartoacyclase.

Alanine (Ala) is a small amino acid whose major spectral peak is a doublet from its methyl group at 1.46 ppm. This doublet overlaps with the lactate doublet, and like lactate, inverts at intermediate TE values (~144 ms). Ala also has a second smaller peak at 3.77 ppm. Ala levels may be elevated in meningiomas, central neurocytomas, and primitive neuroectodermal (PNET) tumors. Elevations are also reported in demyelination and bacterial abscesses.

Branched Chain Amino Acids (leucine, isoleucine, valine) may be identified in patients with various inborn errors of metabolism such as maple syrup urine disease. They are also seen in pyogenic and fungal (but not tuberculous) abscesses. Their principal multiplet peaks lie in the 0.9 – 1.0 range and may invert when intermediate TE values (~144 ms) are used.

Ethanol, the primary ingredient in alcoholic beverages, may be detected in intoxicated patients, characterized by its main triplet peak at 1.19 ppm.

GABA (γ-aminobutyric acid) is the principal inhibitory neurotransmitter in the central nervous system. It has three relatively equal-sized peaks at 1.90, 2.30, and 3.02 ppm. Due to its low concentration compared to other more prominent overlapping (NAA and Cho) peaks, special MRS methods such as spectral editing are needed to identify and resolve GABA resonances.

Galactose, a monosaccharide sugar, and its metabolites galactitol and galactonate, have resonances around 3.7 that may be detected in patients with the inborn error of metabolism, galactosemia.

Glucose, the principal monosaccharide circulating as blood sugar, may be detected during extreme hyperglycemic states such as diabetic ketoacidosis. Principal resonances are at 3.43 and 3.8 ppm.

Glycine (Gly), the smallest the amino acids, has a primary resonance at 3.56 ppm. It is elevated in many brain tumors (glioblastomas, ependymomas, medulloblastomas) and is especially prominent in central neurocytomas. It may also be seen in the spectra of the brain and other organs in nonketotic hyperglycinemia (an inborn error of Gly metabolism).

2-Hydroxyglutarate (2-HG) accumulates in gliomas that have mutations in isocitrate dehydrogenase. Has a small doublet at 2.3 ppm that may be separated from background macromolecules, Glx, and GABA resonances by spectral editing.

Ketone bodies, including acetone (2.22 ppm), acetoacetate (2.26 and 3.46 ppm) and β-hydroxybutyrate (doublet peaks at 1.15 and 1.25 ppm) can be detected in patients on ketogenic diets and in those with diabetic ketoacidosis.

Mannitol, an exogenously administered sugar alcohol used for treatment of increased intracranial pressure and low output renal failure, produces a detectable peak at 3.8 ppm.

Phenylalanine, an aromatic amino acid, has its prominent resonances in the downfield part of the spectrum (i.e., to the left of water) in the 7.31-7.43 range, seen in the inborn error of metabolism, phenylketonuria.

Propylene glycol is a medication solvent (especially for certain anticonvulsants) that may appear in newborns on such drugs. It has a doublet similar to lactate but at 1.13 ppm. It metabolizes to lactate.

Succinate, the anion of succinic acid, is a component of the citric acid cycle. Its singlet peak at 2.4 ppm is often seen together with that of acetate (1.9) and is a marker for anaerobic pyogenic infections as well as cysticercosis. Also elevated in rare enzyme defect succinate dehydrogenase deficiency.

Taurine, a ubiquitous amino-sulfonic acid, is inhibits neural transmission and stabilizes cell membranes. It has two peaks (one at 3.25 ppm, usually obscured by Cho) and a second at 3.42 ppm, just on the left shoulder of Cho. It is elevated in a wide range of disorders, but especially in primitive neuroectodermal tumors (PNET/medulloblastoma/retinoblastoma) and metastatic renal cell cancer.

Trehalose is a disaccharide synthesized by unicellular organisms, especially cryptococcus, seen in fungal abscesses. Spectrum has more than a dozen closely spaced peaks between 3.4 and 3.9 ppm.

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 References
     Behar KL, Rothman DL, Spencer DD, Petroff OAC. Analysis of macromolecule resonances in ¹H NMR spectra of human brain. Magn Reson Med 1994; 32:294-302.
     Birch R, Peet AC, Dehghani H, Wilson M. Influence of macromolecule baseline on ¹H MR spectroscopic imaging reproducibility. Magn Reson Med 2016 (in press).
     Jansen JFA, Backes WH, Nicolay K, Kooi ME. ¹H MR spectroscopy of the brain: absolute quantification of metabolites. Radiology 2006; 240:318-332.
     Govindaraju V, Young K, Maudsley AA. Proton NMR chemical shifts and coupling constants for brain metabolites. NMR Biomed 2000; 13:129-153. (Extensive tables, spectra, and descriptions for just about every metabolite ever detected on a brain MRS study).
     Moffett JR, Ross B, Arun P, et al. N-acetyl aspartate in the CNS: from neurodiagnostics to neurobiology. Prog Neurobiol 2007; 81:89-131. (Everything you wanted to know and more about NAA). 
     Öz G, Alger JR, Barker PB, et al. Clinical proton MR spectroscopy in central nervous system disorders. Radiology 2014; 270:658-679. (good recent review)    
     Safriel Y, Pol-Rodriguez M, Novotny EJ, et al. Reference values for long echo time MR spectroscopy in healthy adults. AJNR Am J Neuroradiol 2005; 26:1439-1445. (regional variations of NAA/Cr and Cho/Cr ratio across the brain).
     Soreni N, Noseworthy MD, Cormier T, et al. Intraindividual variability of striatal ¹H-MRS brain metabolite measurements at 3 T. Magn Reson Imaging 2006; 24:187-194.
     Ulmer S, Backens M, Ahlhelm FJ. Basic principles and clinical applications of magnetic resonance spectroscopy in neuroradiology. J Comput Assist Tomogr 2016; 40:1-16. (good recent review)    
     van der Knaap MS, van der Grond J, van Rijen PC, et al. Age-dependent changes in localized proton and phosphorus MR spectroscopy of the brain. Radiology 1990; 176:509-515.

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Related Questions
     Can MRS peaks be quantified? How accurate is this?
     What is Hunter's angle? What does it mean if the peaks don't line up?  

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