MR Proton SpectroscopyA User-friendly Approach to Interpreting MR Proton

Spectroscopy in the Clinical Setting

Jorge A Vidal, Jeremy Nguyen,

Joseph Nguyen, Derek Staner,

Naveed Ahktar, Lisa Lowe

Saint Luke’s Hospital of Kansas City

104th Annual Meeting of the American Roentgen Ray Society

Introduction

• There are numerous metabolites found in the human brain. 

• Fortunately, only several of them occur in significant quantities and are useful in proton spectroscopic studies. 

• There is evidence that the normal metabolites in the brain vary with according to the patient's age. 

• The changes are most noticeable during the first three years of life. 

• Most of the metabolites are involved in energy metabolism.

• Presented here is a diagram of the major biochemical pathways in the energy production.

NORMAL H BRAIN SPECTRA

• A spectrum of the metabolites is plotted on a two dimensional graph. – The horizontal axis represents the frequencies

(chemical shifts) and the vertical axis represents the concentration of the metabolites. 

• The frequencies are plotted with reference to a stable compound. – The reference compound most often used is

tetramethylsilane (TMS). The chemical shifts are now expressed as parts per million (ppm).

• This approach allows for consistent spectra regardless of the field strength. 

• It also provides a standardization of the spectrum . – TMS is assigned a chemical shift of zero ppm and it

lies to the far most right hand . – The far left end is occupied by water approximately

4.7 ppm. – The area under a peak is contributed by the

concentration of that metabolites. – Therefore, higher or wider peak results from higher

concentration.

• The 1H-MRS spectrum of major metabolites in a normal brain is shown in Fig 1 below:

Major Metabolites in the Brain

• NAA

• Choline

• Creatine

• Lactate

• Glutamine

• Lipid

• Myo-Inositol

N-ACETYLASPARTATE (NAA)

• NAA is the marker of neuronal density and viability. – It is present in both gray and white matter and the difference in

concentration is not clinically significant. – NAA is detected by the its N-acetyl methyl group. – Its concentration appears to decrease with any brain insults such

as infection, ischemic injury, neoplasm, and demyelination process. 

• NAA is not in found in tumors outside the central nervous system (CNS) such as meningioma. 

• NAA is the tallest peak in the proton MR spectrum and it is assigned at 2.0ppm. Additional smaller peaks may be seen at 2.6 and 2.5 ppm. 

• Elevation of NAA is rare and may be found in hyperosmolar state and axonal recovery.

Choline• The choline peak receives contribution from glycerophosphocholine,

phosphocholine, and phosphatidylcholine. – It is the precursor of acetyl choline and phosphatidylcholine. – Acetylcholine is an important neurotransmitter and the latter is an

integral part of cell membrane synthesis. • Disease processes affecting the cell membrane and myelin can lead

to the release of phosphatidylcholine. • Thus, elevation of choline can be seen during ischemic injury,

neoplasm or acute demyelination diseases. • Many brain tumors will lead to elevated choline peak, presumably

associated with their increased cellularity and compression of surrounding brain tissue. 

• Choline is the second largest peak and assigned to 3.2 ppm.

Creatine (Cr)• The Cr peak receives contribution mainly from creatine, and

creatine phosphate. – Note that phospocreatine supplies phosphate to adenosine diphosphate

(ADP) to form adenosine triphosphate (ATP) with the release of creatine. 

• The overall level of total creatine in normal brain is fairly constant. – Reduced Cr level may be seen in pathologic processes such as

neoplasm, ischemic injury, infection or some systemic diseases. – Most metastatic tumors to the brain do not produce creatine since they

do not possess creatine kinase. – Therefore, metastatic tumors should be suspected if there is an

absence of a Cr peak in the proton spectrum. • Cr is the third highest peak and is assigned to 3.03 ppm. It is usually

seen next to the right of choline. An additional peak occurs near 4 ppm but is usually suppressed with water.

Lactate

• Lactate has a molecular structure of CH3-COH2-CO2. • Lactate levels in the brain are normally are very low or

absent. When oxygen supply is depleted, the brain switches to anaerobic respiration for which one end product is lactate. 

• Therefore, elevated lactate peak is a sign of hypoxic tissue. – Low oxygen supply can result from decreased oxygen supply or

increased oxygen requirement. – The former may be seen in vascular insults, or hypoventilation

and the latter may be seen in neoplastic tissue. 

Lactate

• Resonance of lactate consists of two distinct peak (doublet) due to J-J coupling. 

• Lactate peak also occurs at two different locations. – The lower field peak (a doublet) occurs at approximately 1.32

ppm.–  The other peak (a quartet) is seen at 4.1 ppm and this is very

close to the water peak. • usually suppressed during data processing.

• The lactate peak at lower frequency field show a peak inversion for different TE's. – This property serves as an excellent confirmation for the

presence of lactate. The lactate peak is above the baseline at TE of 270 ms and below the baseline at TE of 136 ms. The inversion arises from the weak J-J coupling from the CH3 and CH protons. The coupling constant J is 7Hz.

Myo-Inositol (mI)

• Myo-Inositol is a glucose-like metabolite and it involves primarily in hormone-sensitive neuroreception. It is found mainly in astrocytes and helps to regulate cell volume. 

• Elevated level of mI would be seen where there is glial cell proliferation as in gliosis. – Depressed level of mI would be seen processes

causing glial cell destruction , as in neoplasm, infection or ischemic injury. The main mI peak is assigned to 3.56 ppm and additional peak may be seen at 4.06 ppm.

Lipids

• Lipids are often in composition of triglycerides, phospholipids, and fatty acids. 

• These substances are incorporated into cell membranes and myelin. – Lipid peak should not be seen unless there is destructive

process of the brain including necrosis, inflammation or infection. 

– Lipids have a very short T1 relaxation time and are normally not seen unless short TEs are utilized. 

• The proton lipid peaks occur at several frequencies including 0.8, 1.2, 1.5 and 6.0 ppm. 

• Lipid resonance at 1.2 ppm can sometimes obscure the lactate peak at 1.32 ppm. 

• Fat in the cranium can contaminate the true disease process if the voxels are placed too close the cranium.

Glutamate and Glutamine (Glx)

• Glutamate is an excitatory neurotransmitter in mitochondrial metabolism. 

• Glutamine and glutamate resonate closely together. 

• Their sum is often designated as Glx and is assigned between 2.1 and 2.5 ppm.

Clinical Cases

• The following clinical examples show the diverse range of situations in which MRS may be of benefit.

Case 1

• Hx: 5 month-old female with progressive decreasing muscle tone. – Mother is Japanese and father is Caucasian. 

• MRI– The study shows diffuse white matter changes in both

cerebral hemispheres. T1W show low signal intensity and T2W shows high signal intensity. 

• Diagnosis– Clinical diagnosis of Fukuyama disease

MR Spectroscopy

• Lactate peak (orange arrow) is elevated.

• Lipid peak (blue arrow) is also elevated. 

• Choline peak (yellow arrow) is mildly elevated.

• NAA peak (red arrow) is normal.

Congenital Muscular Dystrophy• Congenital muscular dystrophy (CMD)

– Infants presenting with muscle weakness at birth or early in life.• Confirmed with muscle biopsy.

– There is often associated hypotonia on clinical presentation.• may present with arthrogryposis and associated contractures of the joints. • may show slow progression. Others, however, may have actual functional

improvement, pass various motor milestones and achieve the ability to walk.

• Two categories of Congenital Myotonic Dystrophy have been identified. – Occidental (classic form).

• No apparent Central Nervous System (CNS) involvement. – Fukuyama (FCMD)

• Significant manifestations in the Central Nervous System. 

• Each category of the CMD have sub-categories as follows:– 1. Occidental (no CNS involvement)

• A. Merosin Positive• B. Merosin Negative

– 2. Fukuyama (Subdivided into types 1-4) • A. Classical Type I• B. Congenital Myotonic Dystrophy Type II• C. Atypical Fukuyama (Type III)• D. Atypical Fukuyama (Type IV)

Case 2

• History– 4.5 month old female with seizure and

developmental delay.

• MR findings– White matter disease consistent with Canavan

Disease.– Increased NAA peaks in brain.

Case 2

• Elevated NAA due to accumulation in brain.

Canavan Disease

• Spongiform leukodystrophy– Rare form of leukodystrophy

• autosomal recessive disorder.• Most common in Ashkenazi Jews.

– Deficiency of aspartoacyclase leads to accumulation of N-acetylaspartic acid in the brain, CSF, plasma and urine.

Case 3

• Hx: 11 y/o F with Leukemia , S/P BMT + Cavitary lung lesions + skin lesions

• MRI Fx: – Tiny areas of ring enhancement scattered in brain with larger

areas of surrounding edema.• Wide differential for ring enhancing lesions of the brain.

• Spectroscopy: – Increased Lactate/ Lipid peak + Decreased NAA/ Choline ratio

• Findings consistent with a destructive brain process/ abscess.

• Dx: Combination of imaging findings with MRS suggest focal abscesses. – Child has leukemia and Aspergillosis.

Case 3

• Tiny areas of ring enhancement scattered in brain with larger areas of surrounding edema.

Case 3

• Increased Lactate/ Lipid peak

• Decreased NAA/ Choline ratio

• Dx: Spectroscopy is consistent with a destructive brain process/ abscess; MRI consistent with a focal abscesses; child has leukemia+ Aspergillosis.

Case 4

• 5 month-old male with increased lethargy.

Case 4

–Increased signal in the posterior lentiform nuclei and partially the thalami on DWI.

Case 4

• Spectrum shows elevated choline peak and diminished NAA peak.

• Lactate/lipid peaks are elevated.

Acute Profound Hypoxic Ischemic Injury

• During ischemic injury, the brain cells can revert to anaerobic metabolism due to the absence of oxygen for a brief periods of time. – There will be an accumulation of lactate which results

in acidosis. The acidoctic environment exacerbates further neuronal damage. 

• This is often reflected in the loss of NAA peak.

– The elevation of choline perhaps reflect the destruction of the cell membranes and myelin. 

– It has been reported that elevated lactate and low NAA/Cr ratio can predict the adverse neurological status.

Case 5

• Hx: Progressive Wt loss + apathy in a 4 yr old male

• MRI Fx: abnormal cerebellum (increased T2, decreased T1): atrophy, especially in the central white matter.

• MRS: decreased NAA + increased lactate

• Dx: Proprionic Aciduria

Progressive Wt loss + apathy in a 4 yr old male

• abnormal cerebellum (increased T2, decreased T1): atrophy, especially central white matter,

MRS: decreased NAA & increased lactateDx: Proprionic Aciduria

Case 6

• Hx: 13 mo M w/ left temporal lobe seizures s/p resection of mass. Follow-up of residual disease.

• MRI: – Post-op absence of left temporal lobe, but residual

enhancing tumor along the left tentorium cerebelli.

• MRS:– increased Choline + decreased NAA consistent with

malignancy. – No lactate.

13 mo M with left temporal lobe seizures status post resection of mass. He is here for follow-up of

residual disease.

Post-op absence of left temporal lobe, but residual enhancing tumor along the left tentorium cerebelli.

SV + MV MRS @ 270 msec show increased Cho + decreased NAA consistent with malignancy. No lactate peak.

Dx: Desmoplastic Infantile Ganglioglioma

Case 7

• 51 year old presents with headache and seizures at the Emergency Department.

Case 7

• Cystic appearing lesion in the region of the medial right parietal lobe. – Bright on FLAIR– Low signal intensity on T1W. – Post contrast study reveals a

small nodular enhancement. – Mass effect on the adjacent

lateral ventricle is obvious. • No evidence of

hydrocephalus. 

• Differential considerations:– cystic astrocytoma – hemangioblastoma – epidermoid tumors – cysticercosis

Case 7

• MR Spectra over the lesion shows absence of all normal major brain metabolites.– The high rise at the far

left corner is the water resonance.

• This essentially rules out a primary brain lesion and an extra-cranial lesion should be considered.

Neurocysticercosis

• Caused by the larvae of the pork tapeworm Tenia Solium.– Hematogenous spread.

• Embryo develops into a cysticercus (complex wall surrounding a cavity containing vesicular fluid and scolex)

– CNS involvement in up to 90% of cases.

• MRS is very helpful because a cystic astrocytoma may appear very similar.– However, at least some preservation of NAA peak

should be seen in most primary brain tumors.

Case 8

• 51 year old Caucasian male presents to his primary physician with complaint of seizures.

Case 8

• There is heterogeneous lesion involving the left frontal lobe in the region of Sylvian fissure on T1W with contrast image. 

• FLAIR image shows multiple areas of signal voids interspersed with high signal intensities. – No significant edema is detected.

Case 8

• The major findings of spectroscopy is the absence of all the normal brain metabolites. 

• This is suggestive that the lesion does not arise from brain cells. 

Cavernous Hemangiomas

• A collection of endothelial lined vascular spaces without normal intervening brain between the vessels.

• Can occur throughout the central nervous system– More commonly found in the supratentorial and subcortical

regions. – Can be multiple. 

• Patients are usually asymptomatic– Can present with seizure. 

• Radiographic appearances are contributed by blood products of different ages, calcification and gliosis. 

• T2W sequence usually shows a low signal intensity rim of hemosiderin. 

• Edema is visible when there is hemorrhage.

Mini Quiz

• Try to evaluate these cases before looking at the answer.

Enhancing Suprasellar Mass

• MRS:

– decreased NAA

– increased Choline

• Diagnosis: – Astrocytoma

• MR: High signal intensity mass in the region of the CP angle

• MR SPECT: Increased lipid peak

• Diagnosis:– Cholesterol Granuloma

18 month old female

• MRI: Increased T1 post contrast and FLAIR signal in large left sided mass. Necrosis, and L MCA/ICA encasement

• SPECT: decreased NAA, Increased choline, lactate consistent with a necrotic mass

• Atypical teratoid-rhabdoid tumor

Enhancing Temporal Lobe Mass

• MRS – – Choline peak twice that of

NAA, – Choline peak three times

that of Creatine

• Pathology revealed Grade 3 Astrocytoma

Thank you

• We hope you enjoyed this simple tutorial on MR Proton Spectroscopy.

• Any comments are welcome at:– vidalja@umkc.edu

References

• Atlas SW: Magnetic Resonance Imaging of the Brain and Spine 3rd Edition. Lippincot Williams & Wilkins, 2002.

• Brent WE, Helms CA: Fundamentals of Diagnostic Radiology 2nd Edition, Lippincot Williams & Wilkins, 1999.

• Youssem DM, Grossman RI: Neuroradiology The Requisites 2nd Edition. Mosby, 2003.

• Dahnert W, Radiology Review Manual 4th Edition. Williams and Wilkins, 1999