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.

ObjectiveTo address the variability in prevalence estimates and inconsistencies in potential risk factors for poststroke cognitive impairment (PSCI) using a standardized approach and individual participant data (IPD) from international cohorts in the Stroke and Cognition Consortium (STROKOG) consortium.MethodsWe harmonized data from 13 studies based in 8 countries. Neuropsychological test scores 2 to 6 months after stroke or TIA and appropriate normative data were used to calculate standardized cognitive domain scores. Domain-specific impairment was based on percentile cutoffs from normative groups, and associations between domain scores and risk factors were examined with 1-stage IPD meta-analysis.ResultsIn a combined sample of 3,146 participants admitted to hospital for stroke (97%) or TIA (3%), 44% were impaired in global cognition and 30% to 35% were impaired in individual domains 2 to 6 months after the index event. Diabetes mellitus and a history of stroke were strongly associated with poorer cognitive function after covariate adjustments; hypertension, smoking, and atrial fibrillation had weaker domain-specific associations. While there were no significant differences in domain impairment among ethnoracial groups, some interethnic differences were found in the effects of risk factors on cognition.ConclusionsThis study confirms the high prevalence of PSCI in diverse populations, highlights common risk factors, in particular diabetes mellitus, and points to ethnoracial differences that warrant attention in the development of prevention strategies.

The SORL1 protein plays a protective role against the secretion of the amyloid β peptide, a key event in the pathogeny of Alzheimer's disease. We assessed the impact of SORL1 rare variants in early-onset Alzheimer's disease (EOAD) in a case-control setting. We conducted a whole exome analysis among 484 French EOAD patients and 498 ethnically matched controls. After collapsing rare variants (minor allele frequency ≤1%), we detected an enrichment of disruptive and predicted damaging missense SORL1 variants in cases (odds radio (OR)=5.03, 95% confidence interval (CI)=(2.02-14.99), P=7.49.10(-5)). This enrichment was even stronger when restricting the analysis to the 205 cases with a positive family history (OR=8.86, 95% CI=(3.35-27.31), P=3.82.10(-7)). We conclude that predicted damaging rare SORL1 variants are a strong risk factor for EOAD and that the association signal is mainly driven by cases with positive family history.

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Retrospective, unblinded, nonrandomized comparisons between these 2 strategies have been inconclusive 13 and no randomized evaluation of these strategies has been conducted.14 We hypothesized that the combination of aspirin plus clopidogrel was 25% superior to dose-adjusted warfarin on prevention of new vascular Background and Purpose-Severe atherosclerosis in the aortic arch is associated with a high risk of recurrent vascular events, but the optimal antithrombotic strategy is unclear. Methods-This prospective randomized controlled, open-labeled trial, with blinded end point evaluation (PROBE design) tested superiority of aspirin 75 to 150 mg/d plus clopidogrel 75 mg/d (A+C) over warfarin therapy (international normalized ratio 2-3) in patients with ischemic stroke, transient ischemic attack, or peripheral embolism with plaque in the thoracic aorta >4 mm and no other identified embolic source. The primary end point included cerebral infarction, myocardial infarction, peripheral embolism, vascular death, or intracranial hemorrhage. Follow-up visits occurred at 1 month and then every 4 months post randomization. Results-The trial was stopped after 349 patients were randomized during a period of 8 years and 3 months. After a median follow-up of 3.4 years, the primary end point occurred in 7.6% (13/172) and 11.3% (20/177) of patients on A+C and on warfarin, respectively (log-rank, P=0.2). The adjusted hazard ratio was 0.76 (95% confidence interval, 0.36-1.61; P=0.5). Major hemorrhages including intracranial hemorrhages occurred in 4 and 6 patients in the A+C and warfarin groups, respectively. Vascular deaths occurred in 0 patients in A+C arm compared with 6 (3.4%) patients in the warfarin arm (log-rank, P=0.013). Time in therapeutic range (67% of the time for international normalized ratio 2-3) analysis by tertiles showed no significant differences across groups. Conclusions-Because of lack of power, this trial was inconclusive and results should be taken as hypothesis generating. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00235248.