Abnormalities within normal-appearing grey and white matter (NAGM and NAWM) occur early in the clinical course of multiple sclerosis (MS) and can be detected in-vivo using the magnetisation transfer ratio (MTR). To better characterize the rates of change in both tissues and to ascertain when such changes begin, we serially studied a cohort of minimally disabled, early relapsing-remitting MS patients, using NAGM and NAWM MTR histograms. Twenty-three patients with clinically definite early relapsing-remitting MS (mean disease duration at baseline 1.9 years), and 19 healthy controls were studied. A magnetisation transfer imaging sequence was acquired yearly for two years. Twenty-one patients and 10 controls completed followup. NAWM and NAGM MTR histograms were derived and mean MTR calculated. A hierarchical regression analysis, adjusting for brain parenchymal fraction,was used to assess MTR change over time. MS NAWM and NAGM MTR were significantly reduced in comparison with controls at baseline and, in patients, both measures decreased further during follow-up: (-0.10pu/year, p = 0.001 and -0.18pu/year, p < 0.001 respectively). The rate of MTR decrease was significantly greater in NAGM than NAWM (p = 0.004). Under the assumption that such changes are linear, backward extrapolation of the observed rates of change suggested that NAWM abnormality began before symptom onset. We conclude that increasing MTR abnormalities in NAWM and NAGM are observed early in the course of relapsing-remitting MS. It is now important to investigate whether these measures are predictive of future disability, and consequently, whether MTR could be used as a surrogate marker in therapeutic trials. Abnormalities within normal-appearing gray and white matter (NAGM and NAWM) occur early in the clinical course of multiple sclerosis (MS) and can be detected in-vivo using the magnetisation transfer ratio (MTR). To better characterize the rates of change in both tissues and to ascertain when such changes begin, we serially studied a cohort of minimally disabled, early relapsing-remitting MS patients, using NAGM and NAWM MTR histograms. Twenty-three patients with clinically definite early relapsing-remitting MS A magnetisation transfer imaging sequence was was taken for an annual for two years. Twenty-one patients and 10 controls completed follow. NAWM and NAGM MTR histograms were derived and mean MTR calculated. A hierarchical regression analysis , adjusting for brain parenchymal fraction, was used to assess MTR change over time. MS NAWM and NAGM MTR were significantly reduced in comparison with controls at ba The rate of MTR decrease was significantly greater in NAGM than NAWM (-0.10 pu / year, p = 0.001 and -0.18 pu / year, p <0.001 respectively) (p = 0.004). Under the assumption that such changes are linear, backward extrapolation of the observed rates of change suggested that that NAWM abnormality began before symptom onset. We conclude that increasing MTR abnormalities in NAWM and NAGM are observed early in the course of relapsing -remitting MS. It is now important to investigate either These measures are predictive of future disability, and therefore, whether MTR could be used as a surrogate marker in therapeutic trials.