Lesions in putative language and attention regions are linked to more severe strokes in patients with higher white matter hyperintensity burden

Objective To examine whether high white matter hyperintensity (WMH) burden is associated with greater stroke severity and worse functional outcomes in lesion pattern-specific ways. Methods MR neuroimaging and National Institutes of Health Stroke Scale data at index stroke, as well as modified Rankin Scale (mRS) at 3-6 months post-stroke were obtained from MRI-GENIE study of acute ischemic stroke (AIS) patients. Individual WMH volume was automatically derived from FLAIR-images. Stroke lesions were automatically segmented from DWI-images, spatially normalized and parcellated into atlas-defined brain regions. Stroke lesion effects on AIS severity and unfavorable outcomes (mRS>2) were modeled within a purpose-built machine learning and Bayesian regression framework. In particular, interaction effects between stroke lesions and a high versus low WMH burden were integrated via hierarchical model structures. Models were adjusted for the covariates age, age2, sex, total DWI-lesion and WMH volumes, and comorbidities. Data were split into derivation and validation cohorts. Results A total of 928 AIS patients contributed to stroke severity analyses (mean age: 64.8(14.5), 40% women), 698 patients to functional outcome analyses (mean age: 65.9(14.7), 41% women). Individual stroke lesions were represented in five anatomically distinct left-hemispheric and five right-hemispheric lesion patterns. Across all patients, acute stroke severity was substantially explained by three of these patterns, that were particularly focused on bilateral subcortical and left-hemispherically pronounced cortical regions. In high WMH burden patients, two lesion patterns consistently emerged as more pronounced in case of stroke severity: the first pattern was centered on left-hemispheric insular, opercular and inferior frontal regions, while the second pattern combined right-hemispheric temporo-parietal regions. Bilateral subcortical regions were most relevant in explaining long term unfavorable outcome. No WMH-specific lesion patterns of functional outcomes were substantiated. However, a higher overall WMH burden was associated with higher odds of unfavorable outcomes. Conclusions Higher WMH burden increases stroke severity in case of stroke lesions involving left-hemispheric insular, opercular and inferior frontal regions (potentially linked to language functions) and right-hemispheric temporo-parietal regions (potentially linked to attention). These findings may contribute to augment stroke outcome predictions and motivate a WMH burden and stroke lesion pattern-specific clinical management of AIS patients.