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

Abstract

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 (0.910×10 –3 mm 2 /s vs 0.729×10 –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.

Integrity of normal-appearing white matter and functional outcomes after acute ischemic stroke

“…[3][4][5][23][24][25] There is a growing body of evidence, however, that clinically significant WM injury may exist that is subthreshold of T2 FLAIR detection and that represents a form of microstructural injury. 6,7,21 DTI-based techniques, which are predicated on the quantification of the randomness of water molecule diffusion, are informative on the microstructural integrity of WM. 9,26,27 With respect to NAWM, several studies have used a DTI-based approach to emphasize that the detection of microstructural injury of NAWM precedes the genesis of overt WMH.…”

“…9,26,27 With respect to NAWM, several studies have used a DTI-based approach to emphasize that the detection of microstructural injury of NAWM precedes the genesis of overt WMH. 6,28 A recent study of patients with mild ischemic stroke demonstrated that MD was the most sensitive metric for distinguishing WMH from NAWM and that the accumulation of interstitial fluid is involved in WMH pathogenesis. 17 Therefore, it is reasonable to assume that DTI-based anisotropy metrics of NAWM provide insights into WM composition and, as a result, are informative of functional connectivity and overall cognitive performance.…”

“…[3][4][5] However, a growing body of evidence suggests that macrostructural white matter (WM) disease burden, quantified as WMH on T2-weighted fluid-attenuated inversion recovery (FLAIR) MRI, may not adequately reflect the total extent of WM injury and that microstructural injury to normal-appearing WM (NAWM) can be associated with clinical phenotypes. 6,7 We hypothesized that, in patients with AIS, WM microstructural integrity can be assessed globally on diffusion tensor imaging (DTI) of NAWM in the hemisphere contralateral to the AIS (i.e., contralesional NAWM) and that the metrics of diffusivity will demonstrate association with acute ischemic tissue and long-term functional outcomes. We tested this hypothesis in a large, hospital-based cohort of patients with AIS and brain MRI acquired during the acute-stage evaluation.…”

Isolated, subtle, neurological abnormalities in neurologically and cognitively healthy aging subjects

“…These contradictory data may be explained in two different ways. One option may be that in the brain of these subjects there are ''invisible'' ultrastructural changes in normal appearing white matter that precede the development of imaging-detected WMH [57]. Another possible explanation could be that, although identifiable in conventional imaging, the burden of cerebrovascular pathology must reach a threshold before clinical deficits become evident [14].…”

Small Vessel Disease and the Resting Functional Architecture of the Brain

“…4 As an example, recent studies using diffusion tensor imaging show an association between SVD and microstructural changes within selected white matter tracts, 5,6 changes which have been linked to gait disturbances, 7 decreased performance on cognitive testing, 8 and may precede the development of white matter lesions detected using conventional sequences such as T2 or FLAIR. 9 Despite such advances, a systems-level understanding of how SVD contributes to cognitive dysfunction is missing.…”