• Nick A Weaver, Hugo J Kuijf, Hugo P Aben, Jill Abrigo, Hee-Joon Bae, Mélanie Barbay, Jonathan G Best, Régis Bordet, Francesca M Chappell, ChenChristopher P L HCPLHDepartment of Pharmacology, National University of Singapore, Singapore; Memory, Aging and Cognition Center, National University Health System, Singapore., Thibaut Dondaine, Ruben S van der Giessen, Olivier Godefroy, Bibek Gyanwali, Olivia K L Hamilton, Saima Hilal, Huenges WajerIrene M CIMCDepartment of Neurology and Neurosurgery, University Medical Centre (UMC) Utrecht Brain Center, Utrecht, Netherlands; Experimental Psychology, Helmholtz Institute, Utrecht University, Netherlands., Yeonwook Kang, L Jaap Kappelle, Beom Joon Kim, Sebastian Köhler, de KortPaul L MPLMDepartment of Neurology, Elisabeth Tweesteden Hospital, Tilburg, Netherlands., Peter J Koudstaal, Gregory Kuchcinski, Bonnie Y K Lam, Byung-Chul Lee, Keon-Joo Lee, Jae-Sung Lim, Renaud Lopes, MakinStephen D JSDJInstitute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK., Anne-Marie Mendyk, MokVincent C TVCTDivision of Neurology, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; Therese Pei Fong Chow Research Centre for Prevention of Dementia, Margaret Kam Ling Cheun, Mi Sun Oh, Robert J van Oostenbrugge, Martine Roussel, Lin Shi, Julie Staals, Maria Del C Valdés-Hernández, Narayanaswamy Venketasubramanian, VerheyFrans R JFRJDepartment of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands., Joanna M Wardlaw, David J Werring, Xu Xin, Kyung-Ho Yu, van ZandvoortMartine J EMJEDepartment of Neurology and Neurosurgery, University Medical Centre (UMC) Utrecht Brain Center, Utrecht, Netherlands; Experimental Psychology, Helmholtz Institute, Utrecht University, Netherlands., Lei Zhao, J Matthijs Biesbroek, and Geert Jan Biessels.
• Department of Neurology and Neurosurgery, University Medical Centre (UMC) Utrecht Brain Center, Utrecht, Netherlands.
• Lancet Neurol. 2021 Jun 1; 20 (6): 448459448-459.

BackgroundPost-stroke cognitive impairment (PSCI) occurs in approximately half of people in the first year after stroke. Infarct location is a potential determinant of PSCI, but a comprehensive map of strategic infarct locations predictive of PSCI is unavailable. We aimed to identify infarct locations most strongly predictive of PSCI after acute ischaemic stroke and use this information to develop a prediction model.MethodsIn this large-scale multicohort lesion-symptom mapping study, we pooled and harmonised individual patient data from 12 cohorts through the Meta-analyses on Strategic Lesion Locations for Vascular Cognitive Impairment using Lesion-Symptom Mapping (Meta VCI Map) consortium. The identified cohorts (as of Jan 1, 2019) comprised patients with acute symptomatic infarcts on CT or MRI (with available infarct segmentations) and a cognitive assessment up to 15 months after acute ischaemic stroke onset. PSCI was defined as performance lower than the fifth percentile of local normative data, on at least one cognitive domain on a multidomain neuropsychological assessment or on the Montreal Cognitive Assessment. Voxel-based lesion-symptom mapping (VLSM) was used to calculate voxel-wise odds ratios (ORs) for PSCI that were mapped onto a three-dimensional brain template to visualise PSCI risk per location. For the prediction model of PSCI risk, a location impact score on a 5-point scale was derived from the VLSM results on the basis of the mean voxel-wise coefficient (ln[OR]) within each patient's infarct. We did combined internal-external validation by leave-one-cohort-out cross-validation for all 12 cohorts using logistic regression. Predictive performance of a univariable model with only the location impact score was compared with a multivariable model with addition of other clinical PSCI predictors (age, sex, education, time interval between stroke onset and cognitive assessment, history of stroke, and total infarct volume). Testing of visual ratings was done by three clinicians, and accuracy, inter-rater reliability, and intra-rater reliability were assessed with Cohen's weighted kappa.FindingsIn our sample of 2950 patients (mean age 66·8 years [SD 11·6]; 1157 [39·2%] women), 1286 (43·6%) had PSCI. We achieved high lesion coverage of the brain in our analyses (86·9%). Infarcts in the left frontotemporal lobes, left thalamus, and right parietal lobe were strongly associated with PSCI (after false discovery rate correction, q<0·01; voxel-wise ORs >20). On cross-validation, the location impact score showed good correspondence, based on visual assessment of goodness of fit, between predicted and observed risk of PSCI across cohorts after adjusting for cohort-specific PSCI occurrence. Cross-validations showed that the location impact score by itself had similar performance to the combined model with other PSCI predictors, while allowing for easy visual assessment. Therefore the univariable model with only the location impact score was selected as the final model. Correspondence between visual ratings and actual location impact score (Cohen's weighted kappa: range 0·88-0·92), inter-rater agreement (0·85-0·87), and intra-rater agreement (for a single rater, 0·95) were all high.InterpretationTo the best of our knowledge, 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. Furthermore, we developed a quick and reliable visual rating scale that might in the future be applied by clinicians to identify individual patients at risk of PSCI.FundingThe Netherlands Organisation for Health Research and Development.Copyright © 2021 Elsevier Ltd. All rights reserved.

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