Changes in Normal-Appearing White Matter Precede Development of White Matter Lesions

Background and Purpose-It is unknown whether white matter lesions (WML) develop abruptly in previously normal brain areas, or whether tissue changes are already present before WML become apparent on MRI. We therefore investigated whether development of WML is preceded by quantifiable changes in normal-appearing white matter (NAWM). Methods-In 689 participants from the general population (mean age 67 years), we performed 2 MRI scans (including diffusion tensor imaging and Fluid Attenuation Inversion Recovery [FLAIR] sequences) 3.5 years apart using the same 1.5-T scanner. Using automated tissue segmentation, we identified NAWM at baseline. We assessed which NAWM regions converted into WML during follow-up and differentiated new WML into regions of WML growth and de novo WML. Fractional anisotropy, mean diffusivity, and FLAIR intensity of regions converting to WML and regions of persistent NAWM were compared using 3 approaches: a whole-brain analysis, a regionally matched approach, and a voxel-wise approach. Results-All 3 approaches showed that low fractional anisotropy, high mean diffusivity, and relatively high FLAIR intensity at baseline were associated with WML development during follow-up. Compared with persistent NAWM regions, NAWM regions converting to WML had significantly lower fractional anisotropy (0.337 vs 0.387; P < 0.001), higher mean diffusivity (0.910x10(-3) mm(2)/s vs 0.729x10(-3) mm(2/)s; P < 0.001), and relatively higher normalized FLAIR intensity (1.233 vs -0.340; P < 0.001). This applied to both NAWM developing into growing and de novo WML. Conclusions-White matter changes in NAWM are present and can be quantified on diffusion tensor imaging and FLAIR before WML develop. This suggests that WML develop gradually, and that visually appreciable WML are only the tip of the iceberg of white matter pathology. (Stroke. 2013;44:1037-1042.)