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Magnetisation transfer (MT) imaging provides indirect information on tissue structure abnormalities in areas that otherwise may appear normal on conventional MRI. We determined the evolution of MT changes in normal appearing white matter (NAWM) and lesion on serial examination of 9 multiple sclerosis (MS) patients and age matched controls. The mean NAWM MT ratio (MTR) was found to correlate strongly (R = 0.93) with the length of time since the patient's first clinical presentation and was well characterized by a linear decrease of -0.16%/year (p < 0.0001). The time zero intercept of the NAWM MTR regression was 30.7 ± 0.2%, not different from the average MTR of white matter from controls (30.4 ± 0.2 %). An additional gradual decrease in NAWM MTR was observed 6 to 12 months before the appearance of a new lesion on conventional MRI, while a more precipitous decrease in MTR was seen 2 to 6 months before the lesion appeared. Those lesions that exhibited pre-lesion MTR decreases showed less MTR recovery than lesions which had no pre-lesion MTR decrease. The data suggest that the MTR of NAWM in MS undergoes a slow progressive decrease that starts at disease onset and accelerates rapidly in focal areas just prior to lesion appearance on conventional MRI.