Diffuse microvascular dysfunction and loss of white matter integrity predict poor outcomes in patients with acute ischemic stroke

Abstract

We sought to investigate the relationship between blood-brain barrier (BBB) permeability and microstructural white matter integrity, and their potential impact on long-term functional outcomes in patients with acute ischemic stroke (AIS). We studied 184 AIS subjects with perfusion-weighted MRI (PWI) performed <9 h from last known well time. White matter hyperintensity (WMH), acute infarct, and PWI-derived mean transit time lesion volumes were calculated. Mean BBB leakage rates (K2 coefficient) and mean diffusivity values were measured in contralesional normal-appearing white matter (NAWM). Plasma matrix metalloproteinase-2 (MMP-2) levels were studied at baseline and 48 h. Admission stroke severity was evaluated using the NIH Stroke Scale (NIHSS). Modified Rankin Scale (mRS) was obtained at 90-days post-stroke. We found that higher mean K2 and diffusivity values correlated with age, elevated baseline MMP-2 levels, greater NIHSS and worse 90-day mRS (all p < 0.05). In multivariable analysis, WMH volume was associated with mean K2 ( p = 0.0007) and diffusivity ( p = 0.006) values in contralesional NAWM. In summary, WMH severity measured on brain MRI of AIS patients is associated with metrics of increased BBB permeability and abnormal white matter microstructural integrity. In future studies, these MRI markers of diffuse cerebral microvascular dysfunction may improve prediction of cerebral tissue infarction and functional post-stroke outcomes.

Keywords: White matter lesions; acute ischemic stroke; blood–brain barrier; matrix metalloproteinase-2; outcomes.

Figure 1.

Neuroimaging characteristics of diffuse microvascular dysfunction in a patient with acute ischemic stroke. Top row (panel a–e) demonstrates an example of the normal-appearing white matter region-of-interest in a patient with acute ischemic stroke and white matter hyperintensity volume of 2.36 cm³. (a) FLAIR image, (b) manual WMH outline (red), (c) dilated WMH outline (blue + red), (d) co-registered white matter probability mask, (e) contralesional normal appearing white matter mask (green) calculated as voxels with probability >95% of being white matter AND not in dilated mask (c). Bottom row (panel f–k) demonstrates this patient’s acute (f) DWI, (g) ADC, (h) CBF, (i) CBV, (j) MTT, and (k) K2 map shown overlaid on the FLAIR scan (for clarity only the contralateral hemisphere values are shown). All images are displayed in radiologic format.