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rainguide A brief basic


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Among the new emerging MRI techniques, brain MRS has proved to be of more interest, being readily available & of important clinical applications. In this simplified approach, I tried to provide the minimal required knowledge for the fellow specialist colleagues, otherwise, MRS is a whole science by itself really worth the effort. Also, I preferred to easy-tobetter-tofollow an easy-to-understand & better-to-recall clinical approach rather than starting with the dull sophisticated physics. Notes, illustrations, simple glossary and a list of book & internet references will help better understanding the subject. Hoping you will enjoy as you proceed, I welcome answering any proceed, equestions by e-mail at

Dr Dr
What is MR spectroscopy? MR spectroscopy is the use of magnetic resonance in quantification of various metabolites (chemical composition) and the study of their distribution in different tissues. Rather than displaying MRI proton signals on a gray scale as an image depending on its relative signal strength, MRS displays the quantities as a spectrum. The resonance frequency of each metabolite is represented on a graph and is expressed as parts per million (ppm). This is because the resonance frequency is in MHz or 106 Hz.
MRI Compound Nucleus Concentration Resonances Contrast parameters Spatial resolution Temporal resolution Water (one molecule)

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A normal white matter spectrum demonstrating peak positions of the primary components (N-acetyl aspartate, lipid and lactate, and choline).

MRS Metabolites (various molecules)

1H, 31P

, 13C , 19F

80 Molar One frequency Spin density , relaxation (sub-) millimeter (sub-) seconds

Millimolar Several frequencies (spectrum) Chemical shift Centimeter(s) Minutes

In routine MR imaging, the more edema on a T2 sequence from mobile protons, the brighter the signal on T2. Using MRS, the more metabolite that is present, the taller the peak or greater the area under the peak. Specific metabolites can be located along an x-axis. We can infer that a spectrum of the brain is normal from numerous years of studying such spectra in healthy subjects in whom peak positions and relative intensity ratios have been established.
The different nuclei that can be used with MR spectroscopy include H 1, phosphorus 31, carbon 13, fluorine 19 ,and sodium 23. The hydrogen and phosphorus concentration in central nervous system tissue is high enough to be useful in clinical MR spectroscopy. At this time, hydrogen is best suited for MR spectroscopy because of its: - high concentration, - favorable relaxation time, - high gyromagnetic ratio.

Main metabolites
The Good, The Bad, and The Ugly
Although there are several metabolites included in the spectrum of the MRS, there are three main in the brain: N-acetyl aspartate (NAA), choline (Cho), and the lactate and lipid groups (LL).

NAA = neuronal health (The Good)

N-acetyl aspartate is seen at 2.02 ppm and is believed to be a marker of neuronal health. Originally, decreases in NAA were considered to be due to neuronal destruction, since it was diminished in cases of multiple sclerosis and following trauma. Higher peaks indicate more normal neuronal presence, while diminished peaks occur in situations in which neural damage or replacement has occurred. The only condition where NAA is increased is Canavans disease (genetic defect in the enzymatic breakdown of NAA).

Cho = Tumor marker or cell wall marker (The Bad)

Choline is seen at 3.22 ppm and is present in cell walls of normal brain tissue. As more brain cells are made, one theory suggests the Cho is increased. Active tumor growth will then cause an increase in Cho, since there is abovenormal production of cells. Other processes can release or increase Cho besides tumor; multiple sclerosis or acute infarctions will also release Cho, or cause lysis of cell walls, and increase the concentration of Cho. This can be a transient effect, however, while tumors will demonstrate persistent Cho elevation. We call it The Bad, since tumors show an increase in this metabolite.

LL = Destruction and necrosis (The Ugly)

Lactate (lactic acid) is seen as a doublet (two peaks close to one another) at 1.33 ppm and is a by-product of anaerobic metabolism. Lipids resonate at the 0.9 to 1.2 ppm range. Both are released with cell destruction or synthesized in necrosis. Increased LL can be seen in necrotic tumors, and in stroke due to destruction of cells, and in abscess. It can also be seen in lower concentrations in intermediate tumors. Lactate and lipid peaks are generally present in aggressive disease processes. Normally, lactate is not detectable on human brain MR spectroscopy.

The Cr peak is located at 3.03 ppm and has contributions from Cr, Cr phosphate, GABA, lysine and glutathione. A secondary peak for Cr is at 3.94 ppm. The Cr compounds are involved in energy metabolism via Cr kinase reaction and probably serve as reserves for high-energy phosphates in cell metabolism. Because the Cr peak is relatively resistant to change during disease states when compared with other metabolites, it is usually used in the denominator of Cho/Cr and NAA/Cr ratios. The Cr concentration is increased in hypometabolic disease states and is decreased in hypermetabolic disease states.

The Myoinositol peak is located at 3.56 ppm and is known to decrease in patients with hepatic encephalopathy. It has been suggested that mI be used as a glial cell marker and is increased in Alzheimers disease and demyelinating diseases. The other metabolites identified at low TEs include glutamate, glutamine and alanine. The cerebral levels of glutamine are increased in patients with hepatic encephalopathy and Reyes syndrome.

Types of MRS
Clinical proton MRS techniques include single-voxel spectroscopy (SVS) and multi-voxel chemical shift imaging (CSI). Single voxel spectroscopy produces a single spectrum from a single voxel (Fig a) that is typically 8 cm3 in volume, whereas CSI (Fig b) measures spectra from multiple voxels that are typically 1 cm3 1.5 cm3 in volume. CSI data may be presented in a variety of displays including individual spectra, spectral maps, or colored metabolite images overlaid on anatomical images. The two measurements yield comparable metabolic differences between spectra from the lesion and from the surrounding tissue. However, the relative changes among peaks are slightly different due to the difference in the relative amount of healthy tissue contained in the SVS (8 cm3) and the CSI (1.5 cm3) voxels.

Normal gray and white matter spectra. Note the differences in choline concentration seen at 3.22 ppm.

Data acquisition
Once an MR image is obtained as a localizer image, a volume of interest is selected. If a single voxel is to be analyzed, then a single 3D region of interest is selected. Once the single voxel is obtained, the spectrum is collected based on the amount of protons in the voxel. The proton signals are detected and represented as a free induction decay (FID). A Fourier transform is applied to the FID, converting the temporal information into frequency information. The resonant frequency is then plotted versus signal intensity on a spectrum, instead of the typical gray-scale image. If multiple voxels are to be evaluated, then both a region of interest for evaluation and a region of normal brain are selected for comparison. Of the single-voxel techniques, two commonly used acquisition sequences are stimulated echo acquisition mode (STEAM) and point resolved spectroscopy (PRESS).

With twice the signal of STEAM, PRESS acquisitions are faster; however, spectral baselines are better with STEAM sequences. Care must be taken when identifying voxels of interest (especially for the normal brain comparisons), since significant regional differences in metabolite distributions can be seen in both gray and white matter. Regions to be avoided when selecting voxels include blood, bone, and cysts, since susceptibility artifacts may skew the expected normal molecular distributions. Areas that are difficult to image include the posterior fossa and the spinal cord (both of which encounter problems due to their proximity to bone), as well as tumors containing cystic components, blood, or regions of calcification.

Data analysis
The three-step approach to spectral analysis Step 1: The quality assurance phase. Is it an adequate spectrum? Step 2: Is Hunters angle normal? Step 3: Starting from the right side of the graph, count off the location and check quantities of The Good, The Bad, and The Ugly. These are located on the x axis at 2.02 ppm, 3.22 ppm, and the area from 0.9 to 1.33 ppm.

Small metabolite peaks are not visible in the presence of a large water peak (left spectrum).The effects of inadequate water suppression on the spectral baseline. A (sub-optimal water suppression) and B (adequate suppression with a normalized baseline).

Quality assurance Just as a bad image can make interpretation difficult or impossible for diagnosis, a bad MRS may not be interpretable. Substances that are difficult for MRS to image include bone, blood, cysts, and cerebral spinal fluid (CSF). It is difficult to obtain spectra of bone and blood due to immobile protons (bone) and shim difficulties (blood). Both CSF and cysts can contain lactate products and, thus, may lead to inaccurately elevated lactate or lipids as well. When performing voxel measurements, you should stay clear of these substances in all three imaging planes. Since the area sampled is a voxel, it acquires signal from regions above and below the box that has been placed. Examples of an adequate spectrum include good water suppression; otherwise the water peak on the MRS spectrum is so abundant, it will overshadow the other metabolites. The normal water concentration is 100,000 times the concentration of other metabolites. To detect these metabolites successfully, the signal from water must be suppressed adequately. The water peak located at the far left of the spectrum at 4.7 ppm can be suppressed using chemical shift selective excitation (CHESS) or water elimination Fourier transform technique. At present, CHESS is the most frequently used technique and involves presaturation of water signal using one or more 90 presaturation pulses centered over the water resonance frequency. Using this technique, the water signal can be suppressed by a factor of up to 1000. In contrast, water elimination Fourier transform technique involves a 180 pulse centered over water and is less efficient than CHESS for water suppression. Hunters angle Hunters angle is a term coined from a neurosurgeon, Hunter Sheldon. Instead of doing complex ratios and analysis of the spectra, he simply used his pocket comb. He placed his comb on the spectrum at approximately a 45 angle and connected several of the peaks. If the angle and peaks roughly corresponded to the 45 angle, the curve was probably normal (Fig). If the peaks strayed off the combs angle, the curve was abnormal (Fig). This is a quick, useful method to read MRS and determine normal from abnormal. It is important to remember, however, that this angle was used with STEAM spectra from the brain only.
Examples of abnormal spectra. Note that Hunters angle is seen to be 45 slope in all cases. This aids in the evaluation of normal versus abnormal, though it is not specific for a pathologic diagnosis. The spectra (from left to right), respectively, correspond to a glioblastoma multiforme, a low-grade astrocytoma, stroke, and multiple sclerosis.

Hunters angle

The Good, The Bad, and The Ugly We can look at NAA, Cho, and LL in a more simplified pattern. First, the zero point on the curve is located at the far right of the x-axis in spectral analysis. N-acetyl aspartate is a neuronal marker, thus making it a high, plentiful peak on the curve in normal brain tissue. We can call this The Good marker. If the neuronal health is good, this peak will be the highest peak. It is located at 2.02 ppm on the x-axis. Elevations do not occur (except in patients with Canavans disease). Decreased NAA can be due to replacement with other metabolites (ie, tumor cell walls) or due to unhealthy neurons, as in diffuse axonal injury, multiple sclerosis, or infarction. It can be reversible Next, we moved left on the spectrum to 3.22 ppm on the xaxis, the location of the Cho peak. Remember, we termed Cho The Bad because excess amounts can indicate cell destruction and release of cell walls, or an increase in cell wall synthesis. Excess Cho is an indicator of tumor. It can also be elevated in early phases of cellular destruction and lysis, as in multiple sclerosis and stroke. These can therefore mimic tumor in their early phases. Finally, there are the LL peaks located between 0.9 and 1.33 ppm. This is termed The Ugly because it is an extremely dreadful finding. Lactate and lipid peaks occur when necrosis and a sizeable amount of cell death occurs. It will be the highest peak on the spectrum in most high-grade tumors with marked depression of the NAA peak. Another cause of increased LL peaks occurs with cellular destruction such as stroke.

High-grade tumor. Increased lipid and lactate as well as choline in the presence of decreased N-acetyl aspartate is indicative of a high grade tumor with increased cell walls and necrosis.

Low- to intermediate-grade tumor. Elevated choline due to cell wall synthesis in the absence of significant necrosis (lipid and lactate) elevation.

High-grade tumor: Predominantly The Bad and The Ugly. There is abundant LL and Cho. N-acetyl aspartate is depressed from replacement of neurons with cell wall synthesis and necrosis (Fig). Lower-grade tumor: Predominantly The Bad. There is elevated Cho from tumor cell wall synthesis, but not marked elevation in LL from necrosis. Some NAA depression is present (Fig). The MR spectroscopy spectra of metastases shows increased Cho/Cr and decreased NAA/Cr ratios. The lactate and lipid levels are more likely to be elevated in metastases than in primary brain neoplasms. A typical cerebellopontine angle schwannoma will show the absence of NAA along with elevation of phosphoinositide peak at 3.6 ppm. The absence of NAA along with elevation of alanine peak (1.3 to 1.4 ppm) is often seen in meningiomas. Stroke or radiation necrosis: Predominately The Ugly. There are decreased NAA and Cho peaks with elevation of LL from destruction (Fig). Multiple sclerosis: Loss of The Good. There is loss of NAA peak height, but not much elevation in Cho or LL chronically. Early on, both Cho and LL can be elevated (Fig) and can mimic tumor. A follow-up MRS will usually demonstrate change.

Stroke. Decreased N-acetyl aspartate (neuronal health) and choline (cell walls) with elevation of lipid and lactate from cell destruction.

Multiple sclerosis (MS). Decreased N-acetyl aspartate without elevation of the lipid and lactate peaks or choline (a finding of chronic MS on MRS). In early or acute MS, both lipid and lactate, as well as choline, can be elevated.

Epilepsy: The MR spectroscopy detection of a decrease in NAA coupled with an occasional increase in lactate is useful in detection of the seizure focus in patients with temporal lobe epilepsy. The decrease in NAA corresponds to neuronal loss on histology in these patients. The localization of the seizure focus is helpful in the surgical planning of temporal lobectomy in patients with intractable seizure disorder.

Radiation necrosis versus recurrent tumor. (A) Tumor recurrence. There is elevation of choline as well as lipid and lactate. The choline elevation raises our suspicion of tumor. Note that the baseline water suppression has been altered to ease interpretation. (B) Radiation necrosis. There is elevation only in the lipid lactate area. If the patient has the proper clinical history and the time frame is correct, this is consistent with radiation necrosis and not recurrent tumor. We may elect to follow this with additional MRS and MRI evaluations.

Hemorrhagic amelanotic melanoma metastases in a 75-year-old woman. (A) The T2-weighted image shows acute hematoma (arrow) with associated edema. (B) The proton magnetic resonance spectroscopy shows a single lipid peak (arrow), which was interpreted as no evidence of neoplasm. There are no discernable N-acetylaspartate and choline peaks seen because of magnetic field inhomogeneity induced by paramagnetic blood products. Acquisition parameters: Long echo-time spin-echo (point resolved spectroscopy) sequence with repetition time/echo time = 1500 ms/135 ms.

Other diseases In patients with Alzheimers disease, there is a decrease in NAA levels and hippocampus atrophy, which may be useful in distinguishing this disease from normal aging. There are reports of a decrease in NAA levels and an increase in mI in patients with Alzheimers disease. In patients with hepatic encephalopathy, there is an increase in glutamine, a decrease in Cho, and a decrease in mI concentration. In Parkinsons disease, NAA, Cr, and Cho levels are unchanged but lactate levels are elevated. The MR spectroscopy feature of brain abscess includes increased acetate and succinate levels at 1.92 and 2.42 ppm, respectively.

Brain abscess in a 59-year-old man. (A) The postcontrast T1-weighted image shows a focal necrotic space-occupying lesion in the left temporal lobe with peripheral rim enhancement. (B) The proton magnetic resonance spectroscopy of this lesion shows elevated acetate and succinate levels at 1.92 ppm and 2.42 ppm, respectively (arrows). These are key markers for brain abscess identification (arrows). The broad peak between 1.0 to 1.5 ppm is related to lipid and/or amino acids. Acquisition parameters: Long echo-time spin-echo (point resolved spectroscopy) sequence with repetition time/echo time = 1500 ms/135 ms.

MR spectroscopy is a technically demanding investigation and produces low SNR. The possible causes of poor spectral quality on MR spectroscopy include hemorrhage, postoperative changes, less than 200 acquisitions, small voxel size, and automatic shimming. These causes either result in poor homogenity of the magnetic field or poor SNR, making the interpretation of spectroscopy data unreliable. The presence of hemorrhage and postoperative changes within the volume of interest often leads to poor-quality measurements due to susceptibility effects caused by hemosiderin. The cortical brain lesions located close to the calvaria are often difficult to image on MR spectroscopy because of susceptibility artifacts and contamination from lipids located outside the dura.

A little bite of physics (only if interested)

Chemical shift.what does it mean?

Individual nuclei of the same isotope in a molecule have transition frequencies that differ depending on their chemical environment. This phenomenon, called chemical shift, occurs because the effective magnetic field at a particular nucleus in a molecule is less than the applied magnetic field due to shielding by electrons. So, chemical shift is defined as nuclear shielding / applied magnetic field. An example of resonance chemical shift is observed in the 1H nuclear magnetic resonance spectrum of ethyl acetate (CH3COOCH2CH3; Fig). Resonances at several frequencies are observed in this spectrum. The methylene (CH2) protons are affected by the electron-withdrawing oxygen atoms of the neighboring ester group, and as a result the chemical shift of the methylene proton resonance is significantly different from the chemical shift of the resonances of the protons of the methyl (CH3) groups of ethyl acetate. The two methyl groups are in different chemical environments and therefore give rise to resonances that have different chemical shifts. Because of the dependence of the transition frequency of a nucleus on its chemical environment, chemical shift is diagnostic of the functional group containing the nucleus of interest. The chemical shift (either in hertz or ppm) of a resonance is assigned relative to the chemical shift of a standard reference material. The nuclear magnetic resonance community has agreed to set the chemical shift of certain standard compounds to 0 ppm. For 1H nuclear magnetic resonance, the accepted standard is tetramethylsilane, which is defined to have a chemical shift of 0 ppm.

Some useful definitions

Magnetic resonance (MR) :Absorption or emission of electromagnetic energy by atomic nuclei in a static magnetic field, after excitation by electromagnetic RF radiation at resonant frequency. Fourier transform : Mathematical procedure for reconstructing images from raw data. Voxel: Volume element of the sample to be examined. Voxel size = slice thickness X pixel size Shim : Correction of magnetic field inhomogeneity caused by the magnet itself, ferromagnetic objects, or the patient's body. The basic shim usually involves the introduction of small iron pieces in the magnet. The patient related fine shim is software-controlled and performed using a shim coil.


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