Intravenous thrombolysis within 4.5 hours of symptom discovery in patients with unwitnessed stroke selected by qDFM, who are beyond the recommended time windows, is safe. A randomized trial testing efficacy using qDFM appears feasible and is warranted in patients without large vessel occlusions. Ann Neurol 2018;83:980-993.

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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.

Objective: To characterize the effect of white matter microstructural integrity on cerebral tissue and long-term functional outcomes after acute ischemic stroke (AIS).Methods: Consecutive AIS patients with brain MRI acquired within 48 hours of symptom onset and 90-day modified Rankin Scale (mRS) score were included. Acute infarct volume on diffusion-weighted imaging (DWIv) and white matter hyperintensity volume (WMHv) on T2 fluidattenuated inversion recovery MRI were measured. Median fractional anisotropy (FA), mean diffusivity, radial diffusivity, and axial diffusivity values were calculated within normal-appearing white matter (NAWM) in the hemisphere contralateral to the acute lesion. Regression models were used to assess the association between diffusivity metrics and acute cerebral tissue and longterm functional outcomes in AIS. Level of significance was set at p , 0.05 for all analyses.Results: Among 305 AIS patients with DWIv and mRS score, mean age was 64.4 6 15.9 years, and 183 participants (60%) were male. Median NIH Stroke Scale (NIHSS) score was 3 (interquartile range [IQR] 1-8), and median normalized WMHv was 6.19 cm 3 (IQR 3.0-12.6 cm 3 ). Admission stroke severity (b 5 0.16, p , 0.0001) and small vessel stroke subtype (b 5 21.53, p , 0.0001), but not diffusivity metrics, were independently associated with DWIv. However, median FA in contralesional NAWM was independently associated with mRS score (b 5 29.74, p 5 0.02), along with age, female sex, NIHSS score, and DWIv.Conclusions: FA decrease in NAWM contralateral to the acute infarct is associated with worse mRS category at 90 days after stroke. These data suggest that white matter integrity may contribute to functional recovery after stroke. Neurology ® 2017;88:1701-1708 GLOSSARY AD 5 axial diffusivity; AIS 5 acute ischemic stroke; DTI 5 diffusion tensor imaging; DWIv 5 diffusion-weighted imaging volume; FA 5 fractional anisotropy; FLAIR 5 fluid-attenuated inversion recovery; IQR 5 interquartile range; MD 5 mean diffusivity; MNI 5 Montreal Neurological Institute; mRS 5 modified Rankin Scale; nDWIv 5 normalized diffusion-weighted imaging volume; NAWM 5 normal-appearing white matter; NIHSS 5 NIH Stroke Scale; nWMHv 5 normalized white matter hyperintensity volume; RD 5 radial diffusivity; TOAST 5 Trial of Org 10172 in Acute Stroke Treatment; tPA 5 tissue plasminogen activator; WM 5 white matter; WMH 5 white matter hyperintensity; WMHv 5 white matter hyperintensity volume.The role of white matter hyperintensity (WMH), or leukoaraiosis, in outcomes after acute ischemic stroke (AIS) is increasingly recognized through its link to larger acute infarct lesions, 1 likelihood of infarct expansion, 2 and association with worse functional poststroke outcomes. [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-appear...