Background: Diffusion-tensor (DT) magnetic resonance imaging (MRI) has the po tential to elucidate some characteristics of tissue microstructure inaccessible to other MRI techniques. Objective: To investigate whether normal-appearing bra in tissue abnormalities occur in patients with multiple sclerosis at the earlies t clinical stage and whether their severity is predictive of a short-term disea se evolution by using DT MRI. Design: Forty-five patients and 22 healthy contro l subjects were studied. All patients had had a clinically isolated syndrome wit hin the 3 months preceding study enrollment and paraclinical evidence of disease dissemination in space. During a single session, dual-echo, pulsed-gradient s pin-echo echo-planar, and postgadolinium T1-weighted images of the brain were obtained from each subject. In patients, dual-echo and enhanced images were ob tained after 3 and 12 months, to detect MRI signs of disease dissemination in ti me. An on-study neurological examination was also conducted to ascertain the oc currence of clinical relapses. Mean diffusivity and fractional anisotropy maps w ere derived from DT images. Normal-appearing white matter (N-AWM) and normal- appearing gray matter mean diffusivity and fractional anisotropy histograms were produced and analyzed. Results: During the study period, 29 patients showed MRI evidence of disease dissemination in time. When compared with healthy controls, patients showed higher average NAWM mean diffusivity (P=.01), lower average NAW M mean diffusivity peak height (P < .001), and fractional anisotropy (P < .001). The DT MRI characteristics of patients did not differ between those with and those without disease dissemina tion in time at follow-up. Conclusions: In patients with multiple sclerosis at the earliest clinical stage, the severity of NAWM damage does not predict new le sion formation in the short term, suggesting that the “diffuse”component of ti ssue damage is, at least partially, independent of the “discrete,”predominantl y inflammatory aspects of the disease since its clinical onset. Background: Diffusion-tensor (DT) magnetic resonance imaging (MRI) has the po tential to elucidate some characteristics of tissue microstructure inaccessible to other MRI techniques. Objective: To investigate whether normal-appearing bra in tissue abnormalities occur in patients with multiple sclerosis at the earlies t clinical stage and whether their severity is predictive of a short-term disea se evolution by using DT MRI. Design: Forty-five patients and 22 healthy contro l subjects were studied. All patients had had a clinically isolated syndrome wit hin the During a single session, dual-echo, pulsed-gradient s pin-echo echo-planar, and postgadolinium T1-weighted images of the brain were obtained from each subject. In patients, dual-echo and enhanced images were ob tained after 3 and 12 months, to detect MRI signs of disease dissemination in ti me. An on-study neurological examination wa Mean diffusivity and fractional anisotropy maps derived from DT images. Normal-appearing white matter (N-AWM) and normal-appearing gray matter mean diffusivity and fractional anisotropy histograms were produced and When compared with healthy controls, patients showed higher average NAWM mean diffusivity (P = .01), lower average NAW M mean diffusivity peak height (P <.001), and fractional anisotropy (P <.001). The DT MRI characteristics of patients did not differ between with with and those without disease dissemina- tion in time at follow-up. Conclusions: In patients with multiple sclerosis at the earliest clinical stage, the severity of NAWM damage does not predict new le sion formation in the short term, suggesting that the “diffuse” component of ti ssue damage is, at least partially, independent of the“Discrete,” predominantl y inflammatory aspects of the disease since its clinical onset.