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Molecules in a fluid system are subject to continuous random motion (diffusion). Water molecules within the brain may encounter structures that impede their motion in a particular direction. These structures include the myelin sheath, axonal membranes and subcellular organelles. In this case the diffusion is “hindered” and the value measured is known as the “apparent” diffusion coefficient (ADC). MR images can be sensitised to diffusion by means of large magnetic field gradient pulses, allowing a non-invasive measurement of the ADC. Disruption of the permeability or geometry of structural barriers by pathology alters the diffusion behaviour of water molecules.

Some biological tissues such as brain white matter contain oriented barriers to diffusion. This leads to a property known as anisotropy, and results in a variation in the measured diffusion with tissue direction. White matter fibre tracts consist of collections of similarly aligned myelinated axonal cylinders. Diffusion is much greater along these fibre tracts than across them, due to directional structures including the myelin sheath, axonal membranes, and the neurofilamentous cytoskeleton [Beaulieu 1994]. This directionality of water

diffusion causes fibre tracts to exhibit anisotropic diffusion. Anisotropy is of interest as it is likely to be affected by pathological damage to white matter tracts.

Accurate quantification of diffusion anisotropy requires complete characterization of molecular motion in three directions. The most complete description is provided by a mathematical quantity (a nine element matrix) known as the diffusion tensor [Basserl994]. Measurement of the diffusion tensor is usually performed using echo-planar imaging (EPI) and the diffusion is measured using at least six directions of measurement. From the

diffusion tensor, measures of both the degree and direction of the diffusion throughout the brain may be quantified [Basser 1996], [Pierpaoli et al 1996]. The diffusion tensor has an advantage over simple ADC measurements due to the fact that it is rotationally invariant and independent of patient position or data sequence acquisition.

From the tensor a number of other quantities can be calculated including various anisotropy measures. In white matter, water molecules diffuse preferentially in the direction parallel to axons, being restricted in perpendicular directions [Pierpaoli et al 1996]. This property, termed diffusion anisotropy, may be quantified by two indices: the Fractional Anisotropy (FA) [Basser et al 1996] and Volume Ratio (VR) [Pierpaoli et al 1996]. FA increases with anisotropy and provides the most detailed spatial depiction of anisotropic areas. VR decreases with anisotropy and provides the strongest contrast between low- and high-anisotropy areas, but with decreased anatomical detail. In general, whereas white matter has an oriented microstructure due to similarly aligned fibre tracts with high anisotropy, gray matter is characterized by less ordered tissue and relatively low anisotropy.

Mean Diffusivity (MD) [Basser et al 1996] is another tensor index that measures the magnitude of water diffusion in the tissue without regard to its directonality. MD would therefore not be expected to discriminate between white and gray matter. Cellular structures in the CNS restrict water molecule motion. Pathological processes that modify size, shape and integrity of water filled spaces can result in increased diffusivity. Focal oedema is one of the most prominent changes occurring in acute MS lesions, and might increase diffusivity by reducing the amount of structural barriers to water molecule motion.

Previous studies have also shown an increase in ADC [Larsson et a l 1992b], [Christiansen et al 1993] suggesting a net loss of structural barriers to water motion in MS plaques.

Inflammation, oedema, blood-brain barrier leakage and axonal loss may all contribute to the development of a high ADC in new enhancing lesions [Katz et al 1993], [Trapp et al 1998].

Initial diffusion studies reported higher water diffusion in MS plaques compared to NAWM, and also found evidence that early plaques had the highest diffusion values. The NAWM in MS patients had higher diffusion than normal control white matter. Early studies were limited by head motion, which is an inherent problem in diffusion imaging, and an inability to

measure diffusion in more than three directions. Diffusion Tensor Imaging (DTI) overcame these problems by being theoretically independent of the position of the patient and the pulse sequence used [Basser 1996].

DTI characterizes the microstructural organization of brain tissue in a way that is not possible with other MRI techniques. However, experimental and postmortem studies correlating the DTI changes and histopathology in MS are needed to establish the pathologic basis of the diffusion MRI findings. DTI is likely to illuminate further the pathophysiological changes occurring within MS lesions, particularly when employed in longitudinal studies of lesion evolution together with other MRI techniques including NAA spectroscopy and

magnetization transfer imaging. Future studies should examine the relationship of DTI changes to clinical deficit, and the natural history of diffusion changes within lesions.

Previous studies have shown fractional anisotropy (FA) to be significantly lower and mean diffusivity (MD) significantly higher in patient NAWM [Werring et al 1999], [Christiansen et

al 1993], [Larsson et al 1992b]. Structural abnormalities of NAWM may play a part in the development of irreversible disability in MS. Studies using spectroscopic measurements of NAA have suggested that axonal loss occurs in patient NAWM [Davie et a l 1997] and that this may contribute to progressive disability [Fu et al 1998]. Axonal loss can be expected to show a decrease in FA and an increase in MD.

One study has found that NAWM subsequently involved by enhancement show significantly increasing diffusivity starting up to six months before enhancement appearance [Werring et al 2000]. This suggests that dynamic events, which are closely and temporally related to lesion development, play a part in the changes seen in NAWM before lesion development.

By using DTI to study both lesions and normal appearing brain tissue in patients with early relapsing remitting MS, I hope to evaluate changes in anisotropy and diffusivity at an early stage, and to assess their development over time, as well as their relationship to clinical disability.