Magnetization Transfer and Diffusion Weighted MRI

Magnetization transfer (MT) MRI is based on the interactions between protons in a relatively free environment and those where motion is restricted. Off-resonance irradiation is applied, which saturates the magnetization of the less mobile protons, but this is transferred to the mobile protons, thus reducing the signal intensity from the observable magnetization. Thus, a low MT ratio (MTR) indicates a reduced capacity of the macromolecules in the CNS to exchange magnetization with the surrounding water molecules, reflecting damage to myelin or to the axonal membrane (Fig. 2). The most compelling evidence indicating that markedly decreased MTR values correspond to areas where severe and irreversible tissue loss has occurred comes from a postmortem study showing a strong correlation of MTR values from MS lesions and normal-appearing white matter (NAWM) with the percentage of residual axons and the degree of demyelination (van Waesberghe et al., 1999).

Figure 2 Axial magnetic resonance (MR) images from a patient with multiple sclerosis (MS). The proton-density-weighted scan (A) shows multiple lesions. On the magnetization transfer (MT) map (B), lesions appear as hypointense areas. The degree of hypointensity is related to decrease in MT ratio and indicates damage to the myelin or to the axonal membranes. On the mean diffUsivity (MD) map (C), lesions appear as hyperintense areas. The degree of hyperintensity is related to increase in MD and indicates a loss of structural barriers to water molecular motion. On the fractional anisotropy (FA) map (D), white matter pixels are bright because of the directionality of the white matter fiber tracts. Dark areas corresponding to macroscopic lesions indicate a loss of FA and suggest the presence of structural disorganization.

Figure 2 Axial magnetic resonance (MR) images from a patient with multiple sclerosis (MS). The proton-density-weighted scan (A) shows multiple lesions. On the magnetization transfer (MT) map (B), lesions appear as hypointense areas. The degree of hypointensity is related to decrease in MT ratio and indicates damage to the myelin or to the axonal membranes. On the mean diffUsivity (MD) map (C), lesions appear as hyperintense areas. The degree of hyperintensity is related to increase in MD and indicates a loss of structural barriers to water molecular motion. On the fractional anisotropy (FA) map (D), white matter pixels are bright because of the directionality of the white matter fiber tracts. Dark areas corresponding to macroscopic lesions indicate a loss of FA and suggest the presence of structural disorganization.

Diffusion is the microscopic random translational motion of molecules in a fluid system. Water molecular diffusion can be measured in vivo using DW MRI in terms of an apparent diffusion coefficient (Filippi and Inglese, 2001). Although diffusion is inherently a three-dimensional process, in some tissues with an oriented microstructure such as brain white matter (WM), the molecular mobility is not the same in all directions. This property is called anisotropy and results in a variation of the measured diffu-sivity with tissue measurement direction. White matter fiber tracts consist of aligned myelinated axons; therefore, hindrance of water diffusion is much greater across rather than along the major axis of axonal fibers. Under these conditions, a full characterization of diffusion can be found only in terms of a tensor, a 3 x 3 matrix, where the on-diagonal elements represent the diffusion coefficients along the axes of the reference frame, and the off-diagonal elements account for the correlations between molecular displacement along orthogonal directions (Basser et al., 1994). From the tensor, it is possible to derive some scalar indices (Filippi and Inglese, 2001). These include the mean diffusivity (MD) (equal to one third of the trace of the diffusion tensor), which is affected by cellular size and integrity, and the fractional anisotropy (FA), which reflects the degree of alignment of cellular structures within fiber tracts, as well as their structural integrity (Fig. 2). Studies on neurodegenerative conditions, such as Alzheimer's disease (Bozzali et al., 2001, 2002b; van der Flier et al., 2002, 2003), have shown increased MD and decreased FA both in the gray matter (as a possible direct consequence of neuronal loss) and in the white matter (as a possible consequence of secondary fiber degeneration) of these patients.

Both MT and DW MRI have substantial advantages over cMRI in the study of MS (Filippi et al., 1999; Filippi and Inglese, 2001). First, they provide quantitative information with increased specificity to the heterogeneous substrates of MS pathology. Second, they enable us to quantify the diffuse damage occurring in brain tissues that appear normal on cMRI. Third, with the application of histogram analysis, they can provide multiple parameters influenced by both the cMRI-visible and cMRI-"occult" lesion burdens.

On average, in new enhancing MS lesions (Filippi et al., 1999; Filippi and Inglese, 2001), the MTR drops and the MD increases dramatically when the lesions start to enhance and can show a complete or partial recovery in the subsequent 1 to 6 months (van Waesberghe et al., 1998). These relatively rapid modifications of MTR and MD suggest demyelination and remyelination as the most likely pathological substrate of such short-term changes. In chronic lesions, MT and DW MRI studies have shown variable degrees of MTR and FA reduction and MD increase in T2-visible lesions (Filippi et al., 1999; Filippi and Inglese, 2001). These abnormalities are more pronounced in lesions that appear hypointense on T1-weighted images and in patients with the most disabling courses of the disease (Filippi et al., 1999; Filippi and Inglese, 2001), thus suggesting axonal loss as one of the main possible pathological substrates of intrinsic lesion changes measured using MT and DW MRI. The variability of MTR, MD, and FA values seen in MS lesions also suggests that different proportions of lesions with different degrees of structural changes might contribute to the evolution of the disease. This concept is supported by a 3-year follow-up study (Rocca et al., 1999) showing that newly formed lesions from secondary progressive (SP)-MS patients have more severe MTR deterioration than those from patients with mildly-disabling RR-MS.

Postmortem studies have shown subtle changes in the NAWM from patients with MS, which include diffuse astro-cytic hyperplasia, patchy edema, and perivascular cellular infiltration, as well as axonal damage (Allen and McKeown, 1979; Evangelou et al., 2000b; Bjartmar et al., 2001). Consistent with this finding, reduced MTR and FA values and increased MD values have been found in the NAWM of patients with MS independent of their disease phenotypes (Filippi et al., 1999, 2003a; Filippi and Inglese, 2001). Although all these processes might reduce FA and MTR, myelin and axonal loss should be responsible for the increased MD. Permanent and marked MTR reductions might also correspond to axonal loss as shown by a recent study of the optic nerves of MS patients (Inglese et al., 2002). In this study, very low MTR values were seen in patients with a previous episode of acute optic neuritis (ON) followed by poor clinical recovery. Similar MTR values were also measured from the optic nerve of patients with Leber's hereditary optic neuropathy (Inglese et al., 2002).

The severity of MR-measured NAWM damage has been shown to be associated with increased levels of physical disability and cognitive impairment and to evolve at different rates in the different patient groups, being more pronounced in patients with the progressive forms of the disease (Filippi and Inglese, 2001; Filippi et al., 1999, 2000, 2003a). In patients at presentation with CIS, the extent of normal-appearing brain tissue changes has been found to be an independent predictor of subsequent evolution to clinically definite MS (Iannucci et al., 2000). NAWM-MTR reduction has also been shown to predict the accumulation of clinical disability over the subsequent 5 years in patients with definite MS (Rovaris et al., 2003).

Consistent with postmortem studies (Lumdsen, 1970; Kidd et al., 1999; Peterson et al., 2001; Cifelli et al., 2002), recent studies have shown reduced MTR and increased MD values of the gray matter from patients with MS (Cercignani et al., 2001; Ge et al., 2001; Bozzali et al., 2002a). In patients with RR-MS, these changes worsen over time (Oreja-Guevara et al., 2003) and, as a consequence, they have been found to be more pronounced in patients with the most disabling and progressive disease phenotypes (Bozzali et al., 2002; Ge et al., 2002a). This suggests a progressive accumulation of gray matter damage already in the RR phase of the disease, which was previously unrecognized and which might be one of the factors responsible for the development of brain atrophy (Miller et al., 2002) and for some of the clinical manifestations of the disease, such as neuropsychological impairment (Rao et al., 1989). Recent studies have indeed found a correlation between the severity of cognitive impairment and the degree of MTR (Rovaris et al., 2000) and MD (Rovaris et al., 2002) changes in the gray matter of patients with MS. All of this fits with the notion that gray matter pathology might be an additional factor contributing to the worsening of clinical disability in patients with progressive MS, as a possible consequence of neuronal/axonal damage.

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