White matter hyperintensity burden is associated with neuroaxonal injury in acute ischemic stroke

White matter hyperintensities (WMH) reflect accumulated microvascular brain injury in small vessel disease, yet their impact on acute-phase circulating biomarker profile after ischemic stroke remains poorly defined. We examined whether WMH burden is associated with greater circulating biomarker levels in acute ischemic stroke, independent of infarct size.

We retrospectively analyzed a cohort from a prospective single-center registry of patients with MRI-confirmed ischemic stroke without large-vessel occlusion who were treated with intravenous thrombolysis. WMH and infarct volumes were quantitatively measured on MRI. Circulating neurofilament light chain (NfL) and selected inflammatory and endothelial biomarkers were obtained at the time of thrombolysis. Associations between WMH burden and biomarker levels were assessed using multivariable linear regression.

Among 168 patients (median age 69 years; 39% women), greater WMH volume was independently associated with higher circulating NfL levels (fold-change 1.25, 95% CI 1.12-1.41; p < 0.001), even after adjustment for infarct volume. The standardized effect of WMH volume on NfL was comparable to that of infarct volume. In contrast, associations between WMH burden and inflammatory or endothelial biomarkers were weak and inconsistent after adjustment.

WMH burden is independently associated with higher NfL in the acute phase of ischemic stroke. These findings suggest that NfL levels in the hyperacute stroke setting may reflect acute ischemic injury but also pre-existing chronic microvascular brain damage, supporting consideration of WMH burden when interpreting neuroaxonal biomarkers after stroke.