An echoplanar MR diffusion study of water diffusion in the normal appearing white matter MS and its relationship to water diffusion in focal

lesions

Introduction

Because the NAWM often represents a larger tissue volume than MRI-visible focal lesions, even minor abnormalities of NAWM structure or function may have significant functional effects. This suggestion is supported by data from some

groups demonstrating strong correlations between NAWM abnormalities and clinical deficits (e.g. Fu et al., 1998, van Buchem et al., 1998). It is therefore important to understand the mechanisms by which NAWM abnormalities

originate; a fundamental question is whether they arise independently of focal lesions. If the pathogenetic mechanisms causing NAWM and focal lesions are

closely linked, then the extent of structural damage in NAWM would be expected

to correlate with that in focal lesions. To test this hypothesis a method that is able to detect and quantify subtle pathological changes is required. As we have seen,

MR diffusion imaging is promising in this regard, being sensitive to the size, orientation and integrity of water spaces in tissue. The aims o f the present study

were: firstly, to investigate the relationship between water diffusion in the NAWM

and within focal lesions in a representative cohort of patients with MS; secondly, to assess the spatial distribution of NAWM abnormalities; and thirdly, to

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investigate the diffusion properties of lesions, which were subclassified according

to the presence of T1 hypointensity [indicating severe axonal loss (van

Walderveen et ah, 1998)] or signal enhancement following contrast agent injection [indicating active inflammatory activity (Katz et ah, 1993)].

Although MR diffusion imaging has relatively high spatial resolving power

compared to other techniques (including NAA spectroscopy), its clinical

application has until quite recently been limited by technical factors, including motion artefacts. An EPI technique largely eliminates motion artefact, allowing

the rapid and reliable acquisition of diffusion data from the whole brain (typically in under three minutes). This allows a full assessment of the spatial distribution of

NAWM abnormalities in the brain. The use of a fluid suppression technique reduces the contamination of regions of interest by rapidly diffusing cerebrospinal

fluid (CSF), providing more accurate diffusion measurements (Kwong et ah, 1991).

Patients and methods

Subjects, Forty patients with clinically definite MS (Poser et ah, 1983; Lublin and Reingold, 1996) attending the National Hospital for Neurology and Neurosurgery

were studied with approval from the combined National Hospital and Institute of

Neurology ethics committee after giving informed written consent. No patients

had received any immune-modifying treatment in the three months prior to the study. The clinical groups were defined as follows: benign (n=8) had a relapsing

remitting course and minimal disability at 1 0 years disease duration; relapsing-

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deterioration; secondary progressive (n=13) had progressive deterioration for at least six months following an initial relapsing-remitting course; and primary

progressive (n=1 0) had a progressive deterioration of at least 2 years from onset

without relapses or remissions. A history and full neurological examination was

performed, and the EDSS score (Kurtzke, 1983) was determined by a trained

observer. Fourteen healthy age- and sex-matched controls were studied.

M RI .Conventional imaging. The field of view for all studies was 240mm x

240mm. After a sagittal localiser, fast spin echo images (with proton-density and T2-weighted contrast) were obtained at 28 contiguous 5mm axial slices (matrix size=256x256, TR=2000ms, Teff =14/100). EPI diffusion studies were then

performed without repositioning (see below), followed by multishot EPI scans (matrix size=256x256, TR=200ms, TE=30ms) at 16 x 5mm contiguous axial

locations, matched in position and geometric distortion to the corresponding diffusion-weighted images. Finally, T1-weighted images (matrix size=256x256, TR=540ms, TE=20ms) were acquired five minutes after the administration of Gd- DTPA in all patients except the primary progressive group, and those with known

allergies to contrast media. Previous studies have shown that the yield of

enhancing lesions is low in the primary progressive group (Thompson et al.,

1991).

MRI: Diffusion imaging. A single-shot spin echo EPI diffusion-weighted imaging sequence was used, with an inversion recovery pulse used to suppress the signal

from cerebrospinal fluid (CSF) (Barker et al., 1997), improving lesion conspicuity in areas close to CSF spaces and reducing contamination of regions of interest by

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partial volume of CSF (Kwong et al., 1991). Images were obtained from 16

contiguous 5mm slices. The parameters were as follows: matrix size=128xl28,

TR=5000ms, TI=1265ms, 10 gradient b factors up to 960 smm'^, gradient

strengths 0-22mT/m applied along the three principle gradient axes in turn. The ADCs corresponding to diffusion sensitisation along each axis (ADCx, ADCy and

ADCz) at each voxel were calculated using in-house software, which related the signal attenuation to the b factor (the degree of sensitization to diffusion, including

inherent sensitization due to the imaging gradients) (Stejskal and Tanner, 1965) according to the following:

— — Q'sjp{—bADC^

Sn

where S and So represent the signal in the presence and absence of diffusion sensitive gradients respectively, A D C is the apparent diffusion coefficient and b is

the gradient b factor which depends on the duration and magnitude of the applied

diffusion gradients (LeBihan et al., 1985; LeBihan et al., 1996). From ADCx,

ADCy and ADCz , a directionally-averaged diffusion coefficient, ADCav, was calculated as follows:

A D C + AD C + AD C.