T MRI Studies of Multiple Sclerosis 1521

Role of MRI in Multiple Sclerosis

Multiple sclerosis (MS) is an idiopathic inflammatory demyelinating disease of the central nervous system (CNS) characterized by the presence of widely disseminated lesions throughout the brain and spinal cord [11].

Complementary to the clinical assessment, conventional MRI (cMRI) techniques, such as dual-echo, fluid attenuated inversion recovery (FLAIR), and ^-weighted (with and without post-contrast), provide helpful information for the diagnosis and prognosis of MS, as well as for monitoring disease evolution and therapeutic response to disease-modifying drugs [34,45]. In MS, obtaining MR images of an optimal quality, in terms of resolution and contrast, is a paramount need knowing that, for instance, the diagnostic work-up of patients is based on the ability to identify lesions on MR scans [33].

In addition to the cMRI techniques that are routinely used in clinical practice, a number of non-conventional techniques have been developed in an attempt to overcome the limitations of cMRI [15], such as the lack of specificity to the various pathological substrates of the disease and the inability to quantify the microstruc-

Fig. 15.1. Comparison of3-mm coronal FLAIR images obtained at 1.5 (a, c) and3.0 T (b, d) in patientswith secondaryprogressive MS. Both cortical-subcortical (a, b) and deep internal capsule (c, d) demyelinating lesions are more clearly detectable at 3.0 T (white arrows). Studies were performed on a 1.5- anda3.0-TMR scanner (Intera, Philips Medical System, Best, The Netherlands)

tural damage that is 'occult' to cMRI. These non-conventional techniques include proton magnetic resonance spectroscopy ('H-MRS), magnetization transfer (MT) imaging, diffusion weighted (DW) imaging, diffusion tensor (DT) imaging with fibre tracking, and functional MRI (fMRI). Relative to the currently widely available 1.5 T MR scanners, higher field MRI at 3.0 Tor more will likely improve the quality of these conventional and non-conventional techniques resulting in advances in the management and understanding of MS and other white matter diseases.

Conventional MRI Techniques: Better Lesion Identification and Quantification at Higher Fields

The use of 3.0 T in the clinical practice holds promise regarding image quality improvements which will help identify MS lesions more accurately (Figs. 15.1, 15.2), resulting in a better diagnostic work-up, especially at the earliest stages of the disease when the demonstration of the dissemination of lesions in time and space is vital [33]. Nevertheless, it is legitimate to ask whether there is a real advantage in using 3.0 T MR scanners in

Fig. 15.2. Comparison of 3-mm coronal FLAIR images obtained at 1.5 (a) and3 T (b) in apatient with secondaryprogressive MS. Infratentorial lesions are brighter and more sharply defined at 3.0 T (white arrows). Studies were performed on a 1.5- and a3.0-T MR scanner (Intera, Philips Medical System, Best, The Netherlands)

Fig. 15.2. Comparison of 3-mm coronal FLAIR images obtained at 1.5 (a) and3 T (b) in apatient with secondaryprogressive MS. Infratentorial lesions are brighter and more sharply defined at 3.0 T (white arrows). Studies were performed on a 1.5- and a3.0-T MR scanner (Intera, Philips Medical System, Best, The Netherlands)

Fig. 15.3. Chemical shift imaging 1H-MRS in a patient with migraine. N-Acetylaspartate decrease and choline increase can be measured both in volumes of interest with lesions (1) and NAWM (2). Study performed on a 1.5- and a 3.0-T MR scanner (Intera, Philips Medical System, Best, The Netherlands)

the routine clinical practice of MS considering their higher cost and the risk of'false positive' lesions. Several studies have addressed this issue by comparing image quality, lesion detection and diagnostic value of higher (3.0-4.0 T) and lower (1.5 T) field strength MR scanners in MS [3,13, 26, 48].

The study by Keiper and colleagues [26] was the first to compare the ability to detect white matter abnormalities in MS with conventional fast spin-echo imaging of the brain at 1.5 T and 4.0 T. Within a 1-week period, 15 clinically definite MS patients were scanned at both field strengths. Images were evaluated for lesion identi fication, size, characterization, and subjective resolution. An average of 88 additional lesions were found on images obtained at 4.0 T. Twenty-five lesions identified by consensus on 4.0 T images were not seen on 1.5 T images. Moreover, 4.0 T images showed 56 additional consensually identified lesions, which were indistinct and seen only in retrospect on 1.5 T images. Also, normal perivascular spaces and small perivascular lesions were more easily visualized on 4.0 T images [26]. Bachmann and colleagues [3] compared the diagnostic efficiency of 3.0 T to 1.5 T MRI scanners in a group of 11 patients with MS. Scan times were similar at both field strengths, but at 3.0 T the sequence was modified to take advantage of the increased SNR and consequently acquire more and thinner slices. Qualitatively, 3.0 T was found to be superior to 1.5 T for lesion conspicuity and overall diagnostic value. However, as expected when increasing the magnetic field, more artefacts were present at 3.0 T than at 1.5 T. Significantly more white matter lesions were detected at 3.0 T (n = 162) than at 1.5 T (n = 117) [3]. Using identical acquisition conditions at 1.5 T and 3.0 T, Sicotte and colleagues [48] evaluated the relative sensitivity of MR scanning for MS. Twenty-five MS patients were scanned at both field strengths using fast spin echo, and T1-weighted spoiled gradient recalled acquisition with and without gadolinium contrast injections. Relative to scanning at 1.5 T, the 3.0 T scans showed a 21% increase in the number of detectable contrast enhancing lesions, a 30 % increase in enhancing lesion volume, based on quantification of lesions visible on both scanners, and a 10 % increase in total lesion volume, measured on proton density weighted images [48]. Comparing the total lesion volume and individual lesions observed at 1.5 T and 4.0 T images, Erskine et al. [13] found a 46% increase in the total number of lesions detected and a 60 % increase in the total lesion volume with 4.0 T versus 1.5 T imaging in a group of eight MS patients. Several individual lesions observed at 1.5 T coalesced into larger areas of white matter abnormality in the 4.0 T scans [13].

Together these studies show that higher field MR scanners are able to depict white matter lesions in MS patients that are undetectable at 1.5 T through higher resolution with comparable SNRs and imaging times. Even when the scanning protocols were not optimized to take full advantage of the higher field, 3.0 T scans showed more sensitivity in detecting both Gd-enhanc-ing and non-enhancing white matter lesions. Monitoring the clinical evolution or the therapeutic response to drugs in MS patients is also likely to benefit from the use of higher field MR scanning by enabling the acquisition of images with improved resolution, resulting in increased lesion detection and better quantification. Finally, increased sensitivity for the detection and quantification of MS lesions could improve the correla tion between findings on MR scans and clinical manifestations of the disease that have been so far disappointing [6, 8].

High-Field Magnetic Resonance Spectroscopy: Improved Measurements of Brain Metabolites

1H-MRS is an in vivo technique able to provide metabolic information about the tissues. In MS, measures of W-acetylaspartate (NAA) concentrations are used as a marker of axonal and neuronal damage [1]. Brain NAA is reduced in MS patients relative to healthy controls [18]. The distance between peaks of different chemical species, identified by 1H-MRS, increases linearly with the resonance frequency. Increased SNR allows for shorter scan times, and wider peak separation (spectral resolution), which in turn results in a more accurate peak definition and quantification [39, 47].

'H-MRS allows us to measure the concentrations of the more common metabolites (NAA, choline and creatine) at 1.5 T, but metabolites that are present at lower concentrations, such as glutamine, glutamate and GABA, can be better quantified at higher fields [32].

Using a *H-MRS technique that isolates the glutamate resonance at 3.0 T, Srinivasan and colleagues [49] compared the levels of glutamate between normal subjects and MS patients in different regions of the brain. Glutamate concentrations were significantly higher in acute lesions and normal-appearing white matter (NAWM), but not in chronic lesions. In contrast, levels of NAA were significantly lower in chronic than in acute lesions and NAWM. The choline level was significantly higher in acute than in chronic lesions. Finally increased glial activity was found in MS, with significantly higher myo-inositol levels in acute lesions compared with control white matter. These results support the hypothesis that altered glutamate metabolism is present in MS [49], which might serve as an additional marker of 'destructive' pathological damage. Another study demonstrating the use of high-field *H-MRS in MS was performed by Wylezinska and colleagues [58], who studied 14 patients with relapsing-remitting (RR) MS and 14 age-matched healthy controls with the aim to define the extent of neuronal injury and loss in thalamic grey matter. Both structural and spectroscopy data were acquired on a 3.0 T MR system. A significant 11% decrease in NAA concentrations and a 25 % decrease in normalized thalamic volume were found in MS patients relative to controls. Decreases in thalamic NAA concentration correlated with thalamic volume loss, reflecting the neurodegenerative component ofMS [58]. These are just some examples that illustrate the potential role of high-field *H-MRS in the study of metabolic changes in MS and future 1H-MRS studies in MS might be preferentially conducted at 3.0 T or higher.

Diffusion Tensor Imaging and Fibre Tractography

DT MRI exploits the molecular diffusion of water within biological tissues [29]. Diffusion properties are influenced by the characteristics of the surrounding medium. In MS, the technique is used to detect microscopic abnormalities in the NAWM [5,17, 20, 55], grey matter [37], cervical cord [53], as well as inside lesions [5,7, 27, 55].

Current DT MRI acquisitions on 1.5 T MR scanners can take up to 15 min, which represents a considerable amount of time during which the patient has to remain still. Studies have emphasized the value of DT MRI in MS [7,17,20,27,37,53] and its potential role as a surrogate marker of disease evolution in clinical trials. However, in order to make DT MRI a viable clinical modality, it is important to be able to acquire this additional sequence in a reasonable amount of time without compromising the overall quality of the images. High-field MR scanners are able to reduce the whole brain DT MRI acquisition time to less than 6 min using a singleshot echo planar method [19]. Fibre tractography is a newly developed technique that uses DT MRI to reconstruct white matter fibre tracts [35]. High-field DT MRI will allow better fibre tractography by increasing the resolution of DT images. Reductions in voxel size will also result in a better differentiation of crossing fibres within a voxel. These improvements in fibre tractogra-phy will reinforce the role of this technique in the investigation of diseases affecting the white matter [19].

Anatomical and Physiological Imaging of the Optic Chiasm

Optic neuritis is frequently the initial manifestation of MS. Routine imaging of the optic nerves is a complex task due to the small size of the optic nerve, nerve physiological movement, contamination of the signal from the surrounding tissue (fat, bone, and cerebrospinal fluid), as well as susceptibility effects due to air in neighbouring structures [54]. Higher field MR scanners are likely to overcome at least partially some of these limitations.

In a recent study by Vinogradov and colleagues [54], anatomical, DT and MT MRI at 3.0 T with a custom-designed four-channel head coil were used to study the optic nerve, optic chiasm, and optic tract with the aim of visualizing axonal damage in MS. MT MRI is based on the exchange of magnetization between the protons bound to macromolecules and the protons in free water [57]. Oblique fast spin echo anatomic images were obtained with an in-plane resolution of 0.39x0.52 mm. MT-enhanced 3D gradient-echo time-of-flight images and line scan diffusion images were obtained with an in-plane resolution of 0.78x0.78 mm. Full DT analysis was performed, and apparent diffusion coefficient, fractional anisotropy, and fibre direction maps were obtained. This multimodality approach resulted in high-resolution anatomical and physiological images of the anterior visual pathways that are much harder to obtain at 1.5 T [54].

Pathological Iron Deposition

Several studies suggest that pathological iron deposition in MS could serve as a potential surrogate marker of the destructive disease process [4,12,31,52]. At 3.0 T iron-dependent contrast intrinsic to the brain is much more prominent than at 1.5 T [46], which suggests that future studies aimed at imaging brain iron will be performed on high-field MR systems.

The Future of High-Field Functional MRI in MS

Functional MRI studies at 1.5 T have been conducted in MS patients to study the motor system [30, 40, 42, 44], the visual system [56] and cognition [2,10, 50]. The increased magnetic susceptibility that comes with higher field magnets enhances the blood oxygenation level dependent (BOLD) effect, and the higher SNR strengthens the signal [9]. As a consequence, increased spatial resolution contributes to mapping additional areas and submillimetre structures. Although no study has been published to date on the use of fMRI at 3.0 T in patients with MS, there is no doubt that future functional investigations will be performed at this field strength to study baseline circuitry and connectivity in the MS brain, as well as the mechanisms of neuronal plasticity and compensation related to the extent and location of brain injury [14].

Very High-Field MRI in MS

Although the advantages of MRI performed at 3.0 or 4.0 T relative to those conducted at 1.5 T are already apparent, it is likely that the future of MRI resides in the use of even higher magnetic field MR scanners, despite the associated technological challenges, as has already been done in normal subjects [23, 36, 43] and MS patients [24] at field strengths as high as 8.0 T. The use of an 8.0 T MR scanner allowed Kangarlu and colleagues [24] to show, in vivo, a clear relationship between the demyelinating lesions and the deep venous system, and more precisely that MS plaques are centred on the mi-crovasculature in the white matter [24]. Previously, these observations were only possible on contrast-enhanced MR [51] or on pathological examination of postmortem specimens [16]. Additionally, the cortical microanatomy and location and characteristics of cortical lesions can be visualized at these field strengths in brain samples of newly deceased MS patients [25].

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