Background and Purpose Acute infarct volume, often proposed as a biomarker for evaluating novel interventions for acute ischemic stroke (AIS), correlates only moderately with traditional clinical endpoints such as the modified Rankin Scale (mRS). We hypothesized that the topography of acute stroke lesions on diffusion-weighted MRI (DWI) may provide further information with regard to presenting stroke severity and long-term functional outcomes. Methods Data from a prospective stroke repository were limited to AIS subjects with MRI completed within 48 hours from last known well, admission NIH Stroke Scale (NIHSS), and 3-to-6 months mRS scores. Using voxel-based lesion symptom mapping techniques including age, sex and DWI lesion volume as covariates, statistical maps were calculated to determine the significance of lesion location for clinical outcome and admission stroke severity. Results 490 subjects were analyzed. Acute stroke lesions in the left hemisphere were associated with more severe NIHSS at admission and poor mRS at 3 to 6 months. Specifically, injury to white matter (corona radiata, internal and external capsules, superior longitudinal fasciculus, and uncinate fasciculus), post-central gyrus, putamen, and operculum were implicated in poor mRS. More severe NIHSS involved these regions as well as the amygdala, caudate, pallidum, inferior frontal gyrus, insula, and pre-central gyrus. Conclusions Acute lesion topography provides important insights into anatomical correlates of admission stroke severity and post-stroke outcomes. Future models that account for infarct location in addition to DWI volume may improve stroke outcome prediction and identify patients likely to benefit from aggressive acute intervention and personalized rehabilitation strategies.

Greater WMH burden was associated with SV stroke compared with other ischemic stroke subtypes and, even more strongly, with ICH. These data, from 2 independent samples, support the model that increasing WMHV is a marker of more severe cerebral SV disease and provide further evidence for links between the biology of WMH and SV stroke.

Background White matter hyperintensity (WMH), or leukoaraiosis, is a radiological finding generally assumed to reflect diseased small cerebral vasculature. WMH has significant functional impact through its relationship to cognitive decline and risk of ischemic and hemorrhagic stroke. Accumulating evidence suggests that some manifestations of small vessel disease such as intracerebral hemorrhage (ICH) are associated with low levels of cholesterol. We sought to determine the relationship between hyperlipidemia (HL) and WMH severity in patients with acute ischemic stroke (AIS). Methods We analyzed two independent hospital-based AIS cohorts. Demographic and clinical data were collected prospectively. WMH was measured using semi-automated volumetric image analysis and a semi-quantitative visual grading scale. Univariate and multivariable regression analyses were used to assess the relationship between WMH severity and study variables. Results A total of 631 and 504 subjects in the first and second cohorts, respectively, were included. In univariate analyses, advancing age and hypertension were associated with severity of WMH (p<0.001) in both cohorts. In the multivariable analysis, after controlling for age, gender, and those significant risk factors in the univariate and age-adjusted analyses, patients with a history of HL had less severe WMH in both cohorts (p<0.01). Conclusions Results from two independent cohorts demonstrate that AIS patients with a history of HL have less severe WMH at the time of stroke. These data support the hypothesis that HL may play a relatively protective role on cerebral small vessel disease.

Objective:For 3,670 stroke patients from the United Kingdom, United States, Australia, Belgium, and Italy, we performed a genome-wide meta-analysis of white matter hyperintensity volumes (WMHV) on data imputed to the 1000 Genomes reference dataset to provide insights into disease mechanisms.Methods:We first sought to identify genetic associations with white matter hyperintensities in a stroke population, and then examined whether genetic loci previously linked to WMHV in community populations are also associated in stroke patients. Having established that genetic associations are shared between the 2 populations, we performed a meta-analysis testing which associations with WMHV in stroke-free populations are associated overall when combined with stroke populations.Results:There were no associations at genome-wide significance with WMHV in stroke patients. All previously reported genome-wide significant associations with WMHV in community populations shared direction of effect in stroke patients. In a meta-analysis of the genome-wide significant and suggestive loci (p < 5 × 10−6) from community populations (15 single nucleotide polymorphisms in total) and from stroke patients, 6 independent loci were associated with WMHV in both populations. Four of these are novel associations at the genome-wide level (rs72934505 [NBEAL1], p = 2.2 × 10−8; rs941898 [EVL], p = 4.0 × 10−8; rs962888 [C1QL1], p = 1.1 × 10−8; rs9515201 [COL4A2], p = 6.9 × 10−9).Conclusions:Genetic associations with WMHV are shared in otherwise healthy individuals and patients with stroke, indicating common genetic susceptibility in cerebral small vessel disease.

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...