Background: Post-stroke cognitive impairment (PSCI) occurs in approximately half of ischemic stroke survivors. Infarct location is a potential determinant of PSCI, but a comprehensive map of strategic infarct locations is lacking. In this large-scale multicenter lesion-symptom mapping study, we aimed to identify infarct locations most strongly predictive of PSCI, and use this information to develop a prediction model. Methods:We harmonized individual patient data from twelve cohorts through the Meta-VCI-Map consortium. Patients with acute symptomatic infarcts on CT/MRI and cognitive assessment <1 year poststroke were eligible. PSCI was defined as impairment in ≥1 cognitive domains on neuropsychological assessment or impairment on the Montreal Cognitive Assessment. Voxel-based lesion-symptom mapping (VLSM) was used to calculate voxel-wise odds ratios for PSCI. For the prediction model, a "location impact score" on a five-point scale was derived from the VLSM results. Combined internal-external validation was performed using leave-one-cohort-out cross-validation for all twelve cohorts. Findings:In our combined sample of 2950 patients (age 67±12 years, 39% female), 44% had PSCI. We achieved almost complete lesion coverage of the brain in our analyses (87%). Infarcts in the left frontotemporal lobes, left thalamus, and right parietal lobe were strongly associated with PSCI (False Discovery Rate corrected q<0•01; voxel-wise odds ratios >20). These strategic regions were mapped onto a three-dimensional brain template to visualize PSCI risk per brain region. The location impact score showed good correspondence between predicted and observed risk across cohorts after adjusting for cohortspecific PSCI occurrence. Interpretation:This study provides the first comprehensive map of strategic infarct locations associated with risk of PSCI. A location impact score was derived from this map that robustly predicted PSCI across cohorts and can be applied by clinicians to identify individual patients at risk of PSCI.

Background and Purpose Increased blood-brain barrier (BBB) permeability occurs in cerebral small vessel disease (SVD). It is not known if BBB changes predate progression of SVD. Methods We followed up patients with non-disabling lacunar or cortical stroke and BBB permeability MR imaging following their original stroke. About three years later, we assessed functional outcome (Oxford Handicap Score, OHS, poor outcome defined as 3-6), recurrent neurological events and white matter hyperintensity (WMH) progression on MRI. Results Amongst 70 patients, mean age 68 (SD±11) years, median time to clinical follow up was 39 months (IQR 30-45), median OHS was 2 (IQR 1-3); poor functional outcome was associated with higher baseline WMH score (p<0.001) and increased basal ganglia BBB permeability (p=0.046). Amongst 48 patients with follow-up MRI, WMH progression at follow-up was associated with baseline WMH (ANCOVA p<0.0001) and age (ANCOVA p=0.032). Conclusions Further long term studies to evaluate the role of BBB dysfunction in progression of SVD are required in studies that are large enough to account for key prognostic influences such as baseline WMH and age.

Research has suggested that the retinal vasculature may act as a surrogate marker for diseased cerebral vessels. Retinal vascular parameters were measured using Vessel Assessment and Measurement Platform for Images of the Retina (VAMPIRE) software in two cohorts: (i) community-dwelling older subjects of the Lothian Birth Cohort 1936 (n = 603); and (ii) patients with recent minor ischaemic stroke of the Mild Stroke Study (n = 155). Imaging markers of small vessel disease (SVD) (white matter hyperintensities [WMH] on structural MRI, visual scores and volume; perivascular spaces; lacunes and microbleeds), and vascular risk measures were assessed in both cohorts. We assessed associations between retinal and brain measurements using structural equation modelling and regression analysis. In the Lothian Birth Cohort 1936 arteriolar fractal dimension accounted for 4% of the variance in WMH load. In the Mild Stroke Study lower arteriolar fractal dimension was associated with deep WMH scores (odds ratio [OR] 0.53; 95% CI, 0.32–0.87). No other retinal measure was associated with SVD. Reduced fractal dimension, a measure of vascular complexity, is related to SVD imaging features in older people. The results provide some support for the use of the retinal vasculature in the study of brain microvascular disease.