Magnetization Transfer Imaging

107.1 Techniques

Conventional MRI depends on the contribution to the MR signal of the freely mobile protons of water mol- ecules because of their great abundance and slow re- laxation, leading to a high and sharp resonance with a bandwidth of approximately 20 Hz. Protons bound to macromolecules form a second pool and do not di- rectly contribute to the MR signal because of their rel- atively low concentration and rapid relaxation, result- ing in a low resonance with much broader bandwidth of several thousand hertz. The broad peak of these frequencies is symmetrically arranged around the resonance of mobile protons. Indirectly these bound water molecules can influence the MR signal because there is a physicochemical exchange and cross-relax- ation between the two pools of protons. Dipole–di- pole coupling results in an exchange of magnetiza- tion, called magnetization transfer, where each pool has influence on the relaxation rate of the other. Wolff and Balaban (1989) demonstrated in vitro and vivo that it is possible to selectively excite the bound pool of protons by using a radiofrequency (RF) pulse that is off-resonance for the free water protons. The exci- tation of the macromolecular bound protons leads to transfer of magnetization to the mobile water protons in the magnetization transfer (MT) process. This re- sults in decrease of the MR signal after on-resonance excitation.

The rates of MT between macromolecular bound protons and mobile water protons differ between tis- sues, resulting in different degrees of signal decrease for different tissues, generating a new form of MR contrast. The rate of MT is dependent on a number of factors: the relative proportion of the two pools of protons; the magnetic field strength; the power of the preirradiation with an off-resonance RF prepulse;

and the imaging parameters. The contrast on T

- weighted images is normally already partially deter- mined by magnetization transfer, so the more T

- weighted the image, the smaller the extra MT effect.

The highest MT effect is obtained when an MT pre- pulse is applied to a proton density spin echo or gra- dient echo sequence. The initially used continuous ir- radiation with an off-resonance frequency, adminis- tered with a separate RF unit, is currently replaced by a sinc-shaped pulse wave of short duration, applied between each on-resonance excitation using the main RF transmitter. In conventional multislice MRI a

weak MT effect is always present, because each slice- selective pulse will serve as an off-resonance pulse for the adjacent slices. This effect is stronger when fast MR sequences are used with a high number of refo- cusing pulses.

Myelin forms a major part of the white matter. It is a lipid bilayer, in which proteins are embedded. The major lipids in myelin are cholesterol and glyc- erophospholipids. The lipid bilayer is wrapped in the form of large lamellae around the axons, with a small quantity of extracellular fluid between the layers. This creates a huge surface for interaction between the bound and free water molecules, which facilitates MT.

Compartmentalization of the extracellular fluid fur- ther contributes to the MT effect. The MT effect of the myelin bilipid–water interface is responsible for the bright appearance of myelin on T

-weighted images.

Both cholesterol and cerebrosides are particularly important in determining the myelin bilipid–water interface interactions, which facilitate T

relaxation due to MT. The signal loss of normal white matter due to MT effects ranges from 30% to 50%. It depends on the RF power applied and scan parameters. Gray mat- ter shows a somewhat smaller MT effect than white matter. CSF, containing practically no macromole- cules, shows a 0–2% signal reduction due to MT.

Magnetization transfer imaging (MTI) is used for two reasons. First, MT effects lead to a general signal reduction of the MR image, often referred to as back- ground suppression. The diminution of signal inten- sity of brain tissue can be applied to increase the con- trast between nonenhancing and enhancing tissue in studies with contrast injection. Background suppres- sion with MT is also used in MR angiography.

Secondly, MTI can be used as a separate imaging technique to characterize lesions. In tissue character- ization, the magnetization transfer ratio (MTR) is commonly used. The formula is simple: MTR = [(M

– M

) / M

] ¥ 100%, in which M

is the signal intensity obtained without the MT prepulse, M

or M

the signal intensity with the prepulse applied.

The stronger the MT effect, the higher the MTR. MTR is lower when there is less effect of the macromolecu- lar proton pool. Thus, MTR is a measure of the degree of the structural integrity of brain tissue.

MT can be applied in different ways. MTR mea- surements can be displayed as a MTR map in which each voxel value represents the percentage of signal loss caused by MT (Fig. 107.1). The MTR map allows

Magnetization Transfer Imaging

Chapter 107

voxel-by-voxel measurement or estimation of the average MTR for a specific region of interest. Another approach of MTR data that has attracted much atten- tion is the creation of MTR histograms, either of the whole brain parenchyma or of segmented areas, such as the basal ganglia or the frontal lobe.White and gray matter can also be separated. In a number of postpro- cessing steps the intracranial contents are separated from the skull and orbital contents by a semiautomat- ed software program. In the next step MTRs for every intracranial voxel are calculated. Implementation of a threshold value of 10–20% separates the CSF from the brain parenchyma. Voxels with a value higher than the 10–20% threshold are defined as brain parenchy- ma. The frequency distribution of MTR values can now be displayed as an MTR histogram of the whole brain (Fig. 107.2). The peak height is defined by the highest number of voxels with a certain MTR value.

This measure is influenced by changes in brain tissue related to demyelination, gliosis, and axonal loss, but also by atrophy. The peak value, therefore, has to be normalized by dividing the peak height by the total number of segmented voxels. The relative peak height thus obtained is a measure of the amount of remain- ing brain tissue, independent of brain size and atro-

phy. A measure of atrophy can be obtained by divid- ing the number of voxels representing CSF by the total number of segmented voxels.

A drawback of both 2D and 3D MT is that MT val- ues vary considerably between scanners, even with similar implementations. This is especially important in multicenter trials, and in follow-up studies when a different scanner is used for the same patient.

107.2 Normal Age-Dependent Changes

Important changes in MT have been reported related to brain maturation. With increasing density and complexity of brain tissue, MT changes, mainly ex- pressed as an increase in MTRs. The changes in the MT of white matter run parallel with the progress of myelination. Fiber density or axonal density, however, plays an important role as well. Generally speaking, with increasing age of the infant, there is an increase in MT effect and a higher MTR. This effect is greater in white matter than in gray matter structures. In the neonatal brain MTR values are fairly homogeneously distributed, related to the fact that at that time there is little structural difference between gray and white

Fig. 107.1. The upper row shows a T2-weighted image without MT pulse and a T1-weighted image in a patient with multiple sclerosis. The second row shows on the left side the T2-weighted image with MT pulse. From the images without and with MT pulse, the MTR map can be calculated, which is displayed on the right. From this map MTR values (percentage) can be obtained per voxel or per ROI

matter. MTR values in the unmyelinated neonatal white matter are in the order of 13–19%, followed by a two- to threefold rise to 34–38% with myelination.

Local differences in fiber density and myelin density lead to increasing regional variation in MTR. The highest MTR values after myelination are found in the corpus callosum and posterior limb of the internal capsule, the lowest values in the frontal and occipital white matter; this is probably related to fiber density.

Overall the most rapid changes in MTR in white mat- ter occur during the first year of life. The changes in MTR of gray matter are less conspicuous and level off at the age of 10 months. The peak height of the MTR histogram, however, continues to change over a longer period of time, up to the age of approximately 4 years.

107.3 Magnetization Transfer in Disease States

MT prepulses, MTI, and MTR can be used for a num- ber of clinical applications. First of all, background reduction, as produced by MT prepulses, can be used

to improve the results of MR angiography, where the interest lies in the depiction of arteries and veins and less in the visualization of background structures. For this reason, MT prepulses are a standard part of many MR angiography pulse sequences. Background re- duction can also be applied to improve the effect of contrast enhancement. This can be used to reduce the contrast dose or to have more contrast effect with the same dose, for instance in the search for the number of enhancing multiple sclerosis (MS) lesions or mul- tiplicity of metastases.

The second application is based upon the possibil- ity offered by MT to give a quantitative impression of the structural integrity of brain tissue. In order to as- sess the local structural integrity two types of MT postprocessing are currently in use: a 2D estimation of the MT effect, preferably as a MTR map, or mea- surement of the MT effect in regions of interest. By using whole brain histograms, the lesion load of the entire brain can be assessed. These techniques are ap- plied to disorders characterized by focal or diffuse disintegration of cerebral tissue. They can be used to quantitatively assess the degree of tissue damage in areas that are also abnormal on conventional MR

Chapter 107 Magnetization Transfer Imaging 856

Fig. 107.2. Normalized MTR, ADC and FA histograms from the brain parenchyma of a 38-year-old healthy person that were obtained after removal of cerebrospinal fluid and extracere- bral tissue pixels. Normalized MTR histograms have proven to be very useful in follow-up studies in many disease conditions.

It remains to be seen whether combining histogram analysis of ADC and FA values with MTR histograms will yield valuable information. From Rovaris et al. (2003), with permission

images, but they are also used to assess structures that are normal-appearing on conventional images.

Changes in MT effect may occur in regions where conventional MR techniques do not show abnormali- ties, for instance in normal-appearing white and gray matter in MS, wallerian degeneration, amyotrophic lateral sclerosis, systemic lupus erythematosus, AIDS-related dementia, Alzheimer disease, X-linked adrenoleukodystrophy, and in many other disorders.

In all these disorders, lower MTR values in normal- appearing structures signify a diminution of struc- tural integrity and the presence of a disease state.

MT has been applied most extensively in MS, adding to our understanding of the disease. First of all, lesions visible on conventional images can be studied. MTR values for lesions visible on T

-weight- ed MR images are significantly lower than for nor- mal-appearing white matter, although with a wide range of MTR values. Average MTR for MS lesions was found to be 26.3%, with a lower mean value in chronic progressive (23.3%) than in relapsing-remit- ting MS (27.6%) (Filippi 1999). Follow-up studies show a further reduction of MTR values over time, more pronounced in patients with secondary pro- gressive MS than in those with relapsing-remitting MS. Decreased MTR values were also found in nor- mal-appearing white matter in the neighborhood of focal T

lesions. Using threshold techniques, lesion segmentation can be obtained and the MTR lesion load can be estimated. MTR histogram analysis re- veals that there is a loss of high MTR values and a gain of voxels with low MTR values in MS patients as com- pared to normal persons. The increase in voxels with a low MTR value, however, makes up for only a low percentage (in the order of 15%) of the total decrease in voxels with a high MTR value, suggesting that a higher percentage of “lost” voxels can be attributed to white matter atrophy.

MT has been one of the techniques confirming that normal-appearing white matter in MS is not normal.

With MT, subtle but consistent abnormalities have been found, more pronounced with increasing dis- ability and in progressive MS. MT has also been used to study gray matter involvement. MTR of gray mat- ter is significantly lower in patients with relapsing-re- mitting MS than in controls, confirming that MS is a diffuse disease affecting the whole brain.

A correlative MTR–histopathology study in multi- ple sclerosis has shown that myelin is not the only fac- tor involved in the MT effect.A significant correlation could be demonstrated between MTR and axonal loss (Van Waesberghe et al. 1999), indicating that the MTR reflects not only myelin density but also axonal den- sity.

Table 107.1 shows the relationship between axonal density and MTR. It also demonstrates the relation- ship between hypointensity of MS lesions on T

- weighted images, MTR, and axonal density (Van Waesberghe et al. 1999).

MTR has been applied to compare MS clinical sub- types (relapsing-remitting MS, secondary progressive MS, and primary progressive MS) and to correlate the data with disability scores. While the MTR of white matter is not significantly different for the different MS subtypes, MTR histogram analysis reveals a sig- nificant distinction between relapsing-remitting and progressive MS and between primary and secondary progressive MS. Findings in primary progressive MS are interesting. Primary progressive MS shows few le- sions on conventional MR. MTR histograms show a lower peak height in primary progressive MS than in all the other MS subgroups, with an about normal av- erage brain MTR and normal peak position, suggest- ing that there is a markedly reduced amount of nor- mal brain tissue (Filippi 1999). The correlation be- tween MTR results and disability is better than the correlation between estimations of lesion load and disability. Cognition tests showed correlations with MT parameters of brain atrophy and remaining nor- mal brain tissue (Kalkers et al. 2001). Correlation be- tween gray matter involvement and EDSS is seen as an indication that estimation of gray matter abnor- mality may be useful in assessing clinical disability.

Table 107.1. MTR and axonal density in normal appearing white matter and multiple sclerosis lesions versus degree of T1-hypointensity

Degree of T1-hypointensity MTR (range) % axonal density (range)

normal appearing white matter (n=24) 0.32 (0.26–0.36) 90 (60–100)

isointense (n=18) 0.24 (0.21–0.33) 80 (20–100)

mildly hypointense (n=38) 0.24 (0.16–0.31) 50 (10–100)

severely hypointense (n=53) 0.15 (0.10–0.28) 30 (0–70)

Table 107.2. MTR in different zones of cerebral X-linked adrenoleukodystrophy

Tissue MTR (%)

Unaffected white matter 46

Zone of inflammation and partial myelin loss 35 Zone of severe myelin loss and gliosis 20 (Melhem et al. 1996)

MTR can be used in monitoring of the disease in MS. In view of all the therapeutic trials going on in this disease, objective and quantitative parameters are essential to monitoring the disease course and the efficacy of the treatments applied. For instance, MTR has been used to estimate the effect of interferon be- ta-1a (Kita et al. 2000) and interferon beta-1b (Richert et al. 1998) in MS patients. In these studies MTR was found to be comparable with the more common esti- mation of the number of new enhancing lesions over time.

Another important application of MT is in X- linked adrenoleukodystrophy. Monitoring of the onset of cerebral demyelination is extremely important in young boys. As soon as the first significant signs of progressive cerebral demyelination are found, hemato- poietic stem cell transplantation is performed in an attempt to halt the disease. Because of the significant

morbidity and mortality of the procedure, and the fact that one cannot predict which boy carrying the biochemical and genetic defect will develop the dev- astating cerebral demyelinating disease and which boy will develop adrenomyeloneuropathy, the later- onset and milder form of the disease, hematopoietic stem cell transplantation cannot be performed at an early age as a preventive measure. Careful monitoring at regular intervals is presently the best solution. Con- ventional MRI is important but it has been shown repeatedly that proton MRS, diffusion tensor imag- ing, and MT are more sensitive and are able to demonstrate the onset of the disease and quantify disease progression where conventional MRI does not (yet) show changes. It has been shown in X-linked adrenoleukodystrophy that MTRs correlate closely with the degree of loss of tissue integrity (Melhem et al. 1996).

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