DOI: 10.1093/braincomms/fcae089 ISSN: 2632-1297

Subtle white matter intensity changes on FLAIR imaging in patients with ischemic stroke

Pedro Cougo, Heber Colares, João Gabriel Farinhas, Mariana Hämmerle, Pedro Neves, Raquel Bezerra, Alex Balduíno, Ona Wu, Octavio M Pontes-Neto
  • Neurology
  • Cellular and Molecular Neuroscience
  • Biological Psychiatry
  • Psychiatry and Mental health


Leukoaraiosis is a neuroimaging marker of small-vessel disease that is characterized by high signal intensity on Fluid-Attenuated Inversion Recovery (FLAIR) MRI. There is increasing evidence from pathology and neuroimaging suggesting that the structural abnormalities which characterize leukoaraiosis are actually present within regions of normal-appearing white matter (NAWM), and that the underlying pathophysiology of white matter damage related to small-vessel disease involves blood-brain barrier damage. In this study, we aimed to verify whether leukoaraiosis is associated with elevated signal intensity on FLAIR imaging, a marker of brain tissue free-water accumulation, in normal-appearing white matter.

We performed a cross-sectional study of adult patients admitted to our hospital with a diagnosis of acute ischemic stroke or transient ischemic attack. Leukoaraiosis was segmented using a semi-automated method involving manual outlining and signal thresholding. White matter regions were segmented based on the probabilistic tissue maps from the International Consortium for Brain Mapping 152 atlas. Also, NAWM was further segmented based on voxel-distance from leukoaraiosis borders, resulting in five NAWM strata at increasing voxel-distances from leukoaraiosis. The relationship between normalized mean FLAIR signal intensity on normal-appearing white matter (NAWMM) and leukoaraiosis volume was studied in multivariable statistical analysis using linear mixed modeling, having NAWM strata as a clustering variable.

One-hundred consecutive patients meeting inclusion and exclusion criteria were selected for analysis (53% female, mean age 68 years). NAWMM was higher in the vicinity of leukoaraiosis and progressively lower at increasing distances from leukoaraiosis. In multivariable analysis, NAWMM was positively associated with leukoaraiosis volume and age (B = 0.025 for each leukoaraiosis quartile increase; 95% confidence interval: 0.019–0.030). This association was found similarly across NAWM strata. Voxel maps of NAWMM showed an increase in signal intensity that was not adjacent to leukoaraiosis regions.

Our results show that normal-appearing white matter exhibits subtle signal intensity changes on FLAIR imaging that are related to leukoaraiosis burden. These results suggest that diffuse free water accumulation is likely related to the etiopathogenic processes underlying the development of white matter damage related to small-vessel disease.

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