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White matter hyperintensities (WMH) increase with age, with marked interindividual variation. There is a need for normative data by age and sex, to improve individualized WMH burden assessment. In this study, we pooled cross-sectional data from 15 population-based cohorts (14,876 nondemented individuals, age 18-97 years), through the Meta VCI Map consortium. Whole brain and tract-specific MRI-assessed WMH volumes were calculated in MNI-152 space. We used quantile regression to create centile curves of WMH volume versus age, stratified by sex. Total WMH volume and interindividual variance increased exponentially with age for both sexes, with females showing higher WMH volumes. WMH volume increase with aging was not uniform across the white matter, but instead followed one of three different patterns depending on location. Age- and sex-specific normative data for total and regional WMH volumes were created. Our study provides detailed information on the normal distribution of total and regional WMH volumes across adulthood. The normative data enable a quantitative approach to interpreting total and regional WMH volumes in clinical practice and research settings., Competing Interests: Disclosure Statement PSS has served on the Advisory Committees of Biogen Australia and Roche Australia in 2020–2022. NC serves on DSMBs for AstraZeneca. All other authors report no declarations of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Importance: Cerebral small vessel disease (SVD) is associated with various cerebrovascular outcomes, but data on sex differences in SVD are scarce., Objective: To investigate whether the frequency, severity, and distribution of cerebral microbleeds (CMB), other SVD markers on magnetic resonance imaging (MRI), and outcomes differ by sex., Design, Setting, and Participants: This cohort study used pooled individual patient data from the Microbleeds International Collaborative Network, including patients from 38 prospective cohort studies in 18 countries between 2000 and 2018, with clinical follow-up of at least 3 months (up to 5 years). Participants included patients with acute ischemic stroke or transient ischemic attack with available brain MRI. Data were analyzed from April to December 2023., Main Outcomes and Measures: Outcomes of interest were presence of CMB, lacunes, and severe white matter hyperintensities determined on MRI. Additionally, mortality, recurrent ischemic stroke, and intracranial hemorrhage during follow-up were assessed. Multivariable random-effects logistic regression models, Cox regression, and competing risk regression models were used to investigate sex differences in individual SVD markers, risk of recurrent cerebrovascular events, and death., Results: A total of 20 314 patients (mean [SD] age, 70.1 [12.7] years; 11 721 [57.7%] male) were included, of whom 5649 (27.8%) had CMB. CMB were more frequent in male patients, and this was consistent throughout different age groups, locations, and in multivariable models (female vs male adjusted odds ratio [aOR], 0.86; 95% CI, 0.80-0.92; P < .001). Female patients had fewer lacunes (aOR, 0.82; 95% CI, 0.74-0.90; P < .001) but a higher prevalence of severe white matter hyperintensities (aOR, 1.10; 95% CI, 1.01-1.20; P = .04) compared with male patients. A total of 2419 patients (11.9%) died during a median (IQR) follow-up of 1.4 (0.7-2.5) years. CMB presence was associated with a higher risk of mortality in female patients (hazard ratio, 1.15; 95% CI, 1.02-1.31), but not male patients (hazard ratio, 0.95; 95% CI, 0.84-1.07) (P for interaction = .01). A total of 1113 patients (5.5%) had recurrent ischemic stroke, and 189 patients (0.9%) had recurrent intracranial hemorrhage, with no sex differences., Conclusions and Relevance: This cohort study using pooled individual patient data found varying frequencies of individual SVD markers between female and male patients, indicating potential pathophysiological differences in manifestation and severity of SVD. Further research addressing differences in pathomechanisms and outcomes of SVD between female and male patients is required.

Competing Interests: Disclosures None.

Introduction: We compared the machine learning-derived, MRI-based Alzheimer's disease (AD) resemblance atrophy index (AD-RAI) with plasma neurofilament light chain (NfL) level in predicting conversion of early AD among cognitively unimpaired (CU) and mild cognitive impairment (MCI) subjects., Methods: We recruited participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) who had the following data: clinical features (age, gender, education, Montreal Cognitive Assessment [MoCA]), structural MRI, plasma biomarkers (p-tau 181 , NfL), cerebrospinal fluid biomarkers (CSF) (Aβ42, p-tau 181 ), and apolipoprotein E (APOE) ε4 genotype. We defined AD using CSF Aβ42 (A+) and p-tau 181 (T+). We defined conversion (C+) if a subject progressed to the next syndromal stage within 4 years., Results: Of 589 participants, 96 (16.3%) were A+T+C+. AD-RAI performed better than plasma NfL when added on top of clinical features, plasma p-tau 181 , and APOE ε4 genotype (area under the curve [AUC] = 0.832 vs. AUC = 0.650 among CU, AUC = 0.853 vs. AUC = 0.805 among MCI) in predicting A+T+C+., Discussion: AD-RAI outperformed plasma NfL in predicting syndromal conversion of early AD., Highlights: AD-RAI outperformed plasma NfL in predicting syndromal conversion among early AD. AD-RAI showed better metrics than volumetric hippocampal measures in predicting syndromal conversion. Combining clinical features, plasma p-tau 181 and apolipoprotein E (APOE) with AD-RAI is the best model for predicting syndromal conversion., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Objectives: Cerebral microbleeds are associated with the risks of ischemic stroke and intracranial hemorrhage, causing clinical dilemmas for antithrombotic treatment decisions. We aimed to evaluate the risks of intracranial hemorrhage and ischemic stroke associated with microbleeds in patients with atrial fibrillation treated with vitamin K antagonists, direct oral anticoagulants, antiplatelets, and combination therapy (i.e. concurrent oral anticoagulant and antiplatelet)., Methods: We included patients with documented atrial fibrillation from the pooled individual patient data analysis by the Microbleeds International Collaborative Network. Risks of subsequent intracranial hemorrhage and ischemic stroke were compared between patients with and without microbleeds, stratified by antithrombotic use., Results: A total of 7,839 patients were included. The presence of microbleeds was associated with an increased relative risk of intracranial hemorrhage (adjusted hazard ratio [aHR] = 2.74, 95% confidence interval = 1.76-4.26) and ischemic stroke (aHR = 1.29, 95% confidence interval = 1.04-1.59). For the entire cohort, the absolute incidence of ischemic stroke was higher than intracranial hemorrhage regardless of microbleed burden. However, for the subgroup of patients taking combination of anticoagulant and antiplatelet therapy, the absolute risk of intracranial hemorrhage exceeded that of ischemic stroke in those with 2 to 4 microbleeds (25 vs 12 per 1,000 patient-years) and ≥ 11 microbleeds (94 vs 48 per 1,000 patient-years)., Interpretation: Patients with atrial fibrillation and high burden of microbleeds receiving combination therapy have a tendency of higher rate of intracranial hemorrhage than ischemic stroke, with potential for net harm. Further studies are needed to help optimize stroke preventive strategies in this high-risk group. ANN NEUROL 2023;94:61-74., (© 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Cerebral small vessel disease (SVD) is common during ageing and can present as stroke, cognitive decline, neurobehavioural symptoms, or functional impairment. SVD frequently coexists with neurodegenerative disease, and can exacerbate cognitive and other symptoms and affect activities of daily living. Standards for Reporting Vascular Changes on Neuroimaging 1 (STRIVE-1) categorised and standardised the diverse features of SVD that are visible on structural MRI. Since then, new information on these established SVD markers and novel MRI sequences and imaging features have emerged. As the effect of combined SVD imaging features becomes clearer, a key role for quantitative imaging biomarkers to determine sub-visible tissue damage, subtle abnormalities visible at high-field strength MRI, and lesion-symptom patterns, is also apparent. Together with rapidly emerging machine learning methods, these metrics can more comprehensively capture the effect of SVD on the brain than the structural MRI features alone and serve as intermediary outcomes in clinical trials and future routine practice. Using a similar approach to that adopted in STRIVE-1, we updated the guidance on neuroimaging of vascular changes in studies of ageing and neurodegeneration to create STRIVE-2., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Cerebral small vessel disease (cSVD) is a major cause of stroke and dementia. Previous studies on the prevalence of cSVD are mostly based on single geographically defined cohorts in high-income countries. Studies investigating the prevalence of cSVD in low- and middle-income countries (LMICs) are expanding but have not been systematically assessed., Aim: This study aims to systematically review the prevalence of cSVD in LMICs., Results: Articles were searched from the Ovid MEDLINE and EMBASE databases from 1 January 2000 to 31 March 2022, without language restrictions. Title/abstract screening, full-text review, and data extraction were performed by two to seven independent reviewers. The prevalence of cSVD and study sample size were extracted by pre-defined world regions and health status. The Risk of Bias for Non-randomized Studies tool was used. The protocol was registered on PROSPERO (CRD42022311133). A meta-analysis of proportion was performed to assess the prevalence of different magnetic resonance imaging markers of cSVD, and a meta-regression was performed to investigate associations between cSVD prevalence and type of study, age, and male: female ratio. Of 2743 studies identified, 42 studies spanning 12 global regions were included in the systematic review. Most of the identified studies were from China (n = 23). The median prevalence of moderate-to-severe white matter hyperintensities (WMHs) was 20.5%, 40.5%, and 58.4% in the community, stroke, and dementia groups, respectively. The median prevalence of lacunes was 0.8% and 33.5% in the community and stroke groups. The median prevalence of cerebral microbleeds (CMBs) was 10.7% and 22.4% in the community and stroke groups. The median prevalence of moderate-to-severe perivascular spaces was 25.0% in the community. Meta-regression analyses showed that the weighted median age (51.4 ± 0.0 years old; range: 36.3-80.2) was a significant predictor of the prevalence of moderate-to-severe WMH and lacunes, while the type of study was a significant predictor of the prevalence of CMB. The heterogeneity of studies was high (>95%). Male participants were overrepresented., Conclusions: This systematic review and meta-analysis provide data on cSVD prevalence in LMICs and demonstrated the high prevalence of the condition. cSVD research in LMICs is being published at an increasing rate, especially between 2010 and 2022. More data are particularly needed from Sub-Saharan Africa and Central Europe, Eastern Europe, and Central Asia.

Introduction: Cerebral small vessel disease (SVD) is an important cause of dementia that lacks effective treatment. We evaluated the efficacy and safety of cilostazol, an antiplatelet agent with potential neurovascular protective effects, in slowing the progression of white matter hyperintensities (WMHs) in stroke- and dementia-free subjects harboring confluent WMH on magnetic resonance imaging (MRI)., Methods: In this single-center, randomized, double-blind, placebo-controlled study, we randomized stroke- and dementia-free subjects with confluent WMHs to receive cilostazol or placebo for 2 years in a 1:1 ratio. The primary outcome was change in WMH volume over 2 years. Secondary outcomes were changes in brain volumes, lacunes, cerebral microbleeds, perivascular space, and alterations in white matter microstructural integrity, cognition, motor function, and mood., Results: We recruited 120 subjects from October 27, 2014, to January 21, 2019. A total of 55 subjects in the cilostazol group and 54 subjects in the control group were included for intention-to-treat analysis. At 2-year follow-up, the changes in WMH volume were not statistically different between cilostazol treatment and placebo (0.3±1.0 mL vs -0.1±0.8 mL, p = 0.167). Secondary outcomes, bleeding and vascular events, were also not statistically different between the two groups., Discussion: In this trial with stroke- and dementia-free subjects with confluent WMHs, cilostazol did not impact WMH progression but demonstrated an acceptable safety profile. Future studies should address the treatment effects of cilostazol on subjects at different clinical stages of SVD., Competing Interests: Partially funded by a grant from Otsuka Pharmaceutical (H.K.) Ltd. This funding source had no role in the design, execution, analyses, interpretation of the data, or decision to submit results of this study. Bonaventure Y.M. Ip, Bonnie Y.K. Lam, Vincent M.H. Hui, Lisa W.C. Au, Mandy W.T. Liu, Vivian W.Y. Lee, Winnie C.W. Chu, Thomas W. Leung, Ho Ko, and Vincent C.T. Mok declare that they have no potential conflicts of interest that might be relevant to the contents of the manuscript. L. Shi is the director of BrainNow Medical Technology Limited, which assisted with the quantification of hippocampal ratio. Author disclosures are available in the supporting information., (© 2022 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Purpose: To investigate if network thresholding and raw data harmonization improve consistency of diffusion MRI (dMRI)-based brain networks while also increasing precision and sensitivity to detect disease effects in multicentre datasets., Methods: Brain networks were reconstructed from dMRI of five samples with cerebral small vessel disease (SVD; 629 patients, 166 controls), as a clinically relevant exemplar condition for studies on network integrity. We evaluated consistency of network architecture in age-matched controls, by calculating cross-site differences in connection probability and fractional anisotropy (FA). Subsequently we evaluated precision and sensitivity to disease effects by identifying connections with low FA in sporadic SVD patients relative to controls, using more severely affected patients with a pure form of genetically defined SVD as reference., Results: In controls, thresholding and harmonization improved consistency of network architecture, minimizing cross-site differences in connection probability and FA. In patients relative to controls, thresholding improved precision to detect disrupted connections by removing false positive connections (precision, before: 0.09-0.19; after: 0.38-0.70). Before harmonization, sensitivity was low within individual sites, with few connections surviving multiple testing correction (k = 0-25 connections). Harmonization and pooling improved sensitivity (k = 38), while also achieving higher precision when combined with thresholding (0.97)., Conclusion: We demonstrated that network consistency, precision and sensitivity to detect disease effects in SVD are improved by thresholding and harmonization. We recommend introducing these techniques to leverage large existing multicentre datasets to better understand the impact of disease on brain networks., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Post-stroke cognitive impairment (PSCI) is a common consequence of stroke. Accurate prediction of PSCI risk is challenging. The recently developed network impact score, which integrates information on infarct location and size with brain network topology, may improve PSCI risk prediction., Aims: To determine if the network impact score is an independent predictor of PSCI, and of cognitive recovery or decline., Methods: We pooled data from patients with acute ischemic stroke from 12 cohorts through the Meta VCI Map consortium. PSCI was defined as impairment in ≥ 1 cognitive domain on neuropsychological examination, or abnormal Montreal Cognitive Assessment. Cognitive recovery was defined as conversion from PSCI < 3 months post-stroke to no PSCI at follow-up, and cognitive decline as conversion from no PSCI to PSCI. The network impact score was related to serial measures of PSCI using Generalized Estimating Equations (GEE) models, and to PSCI stratified according to post-stroke interval (<3, 3-12, 12-24, >24 months) and cognitive recovery or decline using logistic regression. Models were adjusted for age, sex, education, prior stroke, infarct volume, and study site., Results: We included 2341 patients with 4657 cognitive assessments. PSCI was present in 398/844 patients (47%) <3 months, 709/1640 (43%) at 3-12 months, 243/853 (28%) at 12-24 months, and 208/522 (40%) >24 months. Cognitive recovery occurred in 64/181 (35%) patients and cognitive decline in 26/287 (9%). The network impact score predicted PSCI in the univariable (OR 1.50, 95%CI 1.34-1.68) and multivariable (OR 1.27, 95%CI 1.10-1.46) GEE model, with similar ORs in the logistic regression models for specified post-stroke intervals. The network impact score was not associated with cognitive recovery or decline., Conclusions: The network impact score is an independent predictor of PSCI. As such, the network impact score may contribute to a more precise and individualized cognitive prognostication in patients with ischemic stroke. Future studies should address if multimodal prediction models, combining the network impact score with demographics, clinical characteristics and other advanced brain imaging biomarkers, will provide accurate individualized prediction of PSCI. A tool for calculating the network impact score is freely available at https://metavcimap.org/features/software-tools/lsm-viewer/., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: The benefit and risk of aerobic exercise among older people harboring advanced cerebral small vessel disease (CSVD) upon cognition, mood, and motor functions are unknown., Methods: This rater-blind randomized trial examined effects of a 24-week aerobic exercise training (60 min/session, twice/week) upon clinical (cognition, mood, motor functions) and hemodynamic (pulse pressure [PP], blood pressure [BP], pulsatility index) measures in older people harboring moderate to severe CSVD, as evidenced by confluent white matter hyperintensity and/or ≥2 lacunes on magnetic resonance imaging. We further investigated interactions between treatment conditions and hemodynamics measures., Results: Fifty-three and 54 subjects were randomized into the active and control group, respectively. There was no between-group difference in any of the clinical outcomes. The active group had a greater between-group reduction in systolic BP and PP than the control group. Within-group comparison showed that global cognition of the active group remained similar at end of the study compared to baseline, whereas it declined significantly in the control group. We observed "diverging" interaction effects in that greater reduction in systolic BP/PP was associated with greater improvement in memory functions and global cognition but worsening in processing speed in the active group. Side effects were comparable between the two groups., Discussion: Future study should investigate the mechanisms of the diverging impacts of aerobic exercise upon different cognitive domains so that the benefit-risk ratio of aerobic exercise in older people harboring more advanced CSVD can be better defined., Competing Interests: In the past 36 months, Adrian Wong reports payment from Hong Kong Court (payment made to him). Margaret Kit Yi Mak reports conference attendance support from The Hong Kong Polytechnic University to attend the XXVI World Congress on Parkinson's Disease and Related Disorders May 1–4, 2021. Linda Chiu Wa Lam reports consulting fees from the second expert Colloquium on Early Alzheimer's Disease organized by Eisai Pharmaceutical (zoom meeting in 2020); and giving a lecture and preparing a newsletter article on mental disorders for dentists for the Hong Kong Dental Association (2020); and she is a member of the Advisory Committee on Mental Health at the Food and Health Bureau of the HKSAR government. Sin Ki Yeung reports the provision of reading materials by the professor for the submitted work. Lin Shi reports grants from Hong Kong General Research Fund and Innovation and Technology Fund. Thomas Wai Hong Leung is the president of Hong Kong Neurological Society (unpaid). Yannie Oi Yan Soo reports grants from Hong Kong Health and Medical Research Fund (payment made to CUHK) and Emerging Markets Thrombosis Investigator‐Initiated Research Program from Pfizer (payment made to CUHK); and honorarium for being a speaker from Amgen (payment made to her), honorarium for being a speaker from Daiichi and Boehringer Ingelheim (Hong Kong) Ltd (payment made to CUHK); and support for conference attendance by Hong Kong Neurological and Hong Kong Stroke Societies (no direct payment involved). Timothy Chi Yui Kwok is the director of Jockey Club Centre for positive ageing, Hong Kong; reports honorarium for attending a hearing for guardianship board, Hong Kong; and payment from Hong Kong government for expert report for coroner office; and donation for research (donation made to CUHK). Ho Ko reports grants from Croucher Innovation Award, Collaborative Research Fund of the Research Grants Council, Hong Kong and Area of Excellence Scheme of the Research Grants Council, Hong Kong (payments made to CUHK); and consulting fees from Videns Incorporation Limited. He has patents on the identifications of new potential disease‐modifying therapeutics for Niemann‐Pick disease type C, a method for slowing down brain aging, and new methods for achieving rapid and deep immunostaining. All other authors declare no financial disclosures or conflicts of interest., (© 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Age-related white matter lesion (WML) is considered a manifestation of sporadic cerebral small vessel disease and an important pathological substrate for dementia. Asia is notable for its large population with a looming dementia epidemic. Yet, the burden of WML and its associated risk factors across different Asian societies are unknown. Subjects from 9 Asian cities (Bangkok, Bandung, Beijing, Bengaluru, Hong Kong, Kaohsiung, Manila, Seoul, and Singapore) were recruited (n = 5701) and classified into (i) stroke/transient ischemic attack (TIA), (ii) Alzheimer's disease (AD)/mild cognitive impairment (MCI), or (iii) control groups. Data on vascular risk factors and cognitive performance were collected. The severity of WML was visually rated on MRI or CT. The prevalence of moderate-to-severe WML was the highest in subjects with stroke/TIA (43.3%). Bandung Indonesia showed the highest prevalence of WML, adjusted for age, sex, education, disease groups, and imaging modality. Hypertension and hyperlipidemia were significant risk factors for WML, and WML was negatively associated with MMSE in all groups. WML is highly prevalent in Asia and is associated with increasing age, hypertension, hyperlipidemia, and worse cognitive performance. Concerted efforts to prevent WML will alleviate the huge dementia burden in the rapidly aging Asian societies.

Background: Post-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., Methods: In 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., Findings: In 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., Interpretation: To 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., Funding: The Netherlands Organisation for Health Research and Development., Competing Interests: Declaration of interests H-JB reports grants from Bristol-Myers Squibb Korea, Chong Kun Dang Pharmaceutical, Dong-A Pharmaceutical, AstraZeneca Korea, Bayer, Daiichi Sankyo, Yuhan, Jeil Pharmaceutical, Korean Drug, Shinpoong Pharmaceutical, Servier Korea, JLK Inspection, and Samjin Pharmaceutical, grants and personal fees from Shire Korea and Eisai Korea, and personal fees from Amgen Korea and Otsuka Korea, outside the submitted work. DJW reports personal fees from Bayer, Alnylam Pharmaceuticals, and Portola, outside the submitted work. OG reports grants from Amiens University Hospital and the French Ministry of Health, during the conduct of the study; and during the last 5 years OG has served on scientific advisory boards and as a speaker for Novartis, CSL-Behring, Biogen, Genzyme, Lilly, Bristol-Myers Squibb, Boehringer-Ingelheim, Covidien, Teva Santé, and Astra Zeneca, outside the submitted work. MB has received funding for travel and meetings from Teva Santé, Bristol-Myers Squibb, Roche, Pfizer, Sanofi-Aventis France, Isis Perfusion Nord, and Amgen. GJB reports grants from The Netherlands Organisation for Health Research and Development (ZonMW), during the conduct of the study. JMW reports grants from the Wellcome Trust, Row Fogo Charitable Trust, Chest Heart Stroke Scotland, and the UK Medical Research Council, during the conduct of the study; and grants from Fondation Leducq, EU Horizon 2020 (SVDs@target project, grant agreement number 666881), the British Heart Foundation, and the UK Stroke Association, outside the submitted work. HPA reports grants from ZonMW (grant number 842003011), during the conduct of the study. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Alzheimer's Disease-resemblance atrophy index (AD-RAI) is an MRI-based machine learning derived biomarker that was developed to reflect the characteristic brain atrophy associated with AD. Recent study showed that AD-RAI (≥0.5) had the best performance in predicting conversion from mild cognitive impairment (MCI) to dementia and from cognitively unimpaired (CU) to MCI. We aimed to validate the performance of AD-RAI in detecting preclinical and prodromal AD. We recruited 128 subjects (MCI=50, CU=78) from two cohorts: CU-SEEDS and ADNI. Amyloid (A+) and tau (T+) status were confirmed by PET ( 11 C-PIB, 18 F-T807) or CSF analysis. We investigated the performance of AD-RAI in detecting preclinical and prodromal AD (i.e. A+T+) among MCI and CU subjects and compared its performance with that of hippocampal measures. AD-RAI achieved the best metrics among all subjects (sensitivity 0.74, specificity 0.91, accuracy 85.94%) and among MCI subjects (sensitivity 0.92, specificity 0.81, accuracy 86.00%) in detecting A+T+ subjects over other measures. Among CU subjects, AD-RAI yielded the best specificity (0.95) and accuracy (85.90%) over other measures, while hippocampal volume achieved a higher sensitivity (0.73) than AD-RAI (0.47) in detecting preclinical AD. These results showed the potential of AD-RAI in the detection of early AD, in particular at the prodromal stage.

Background: Balancing the risks of recurrent ischaemic stroke and intracranial haemorrhage is important for patients treated with antithrombotic therapy after ischaemic stroke or transient ischaemic attack. However, existing predictive models offer insufficient performance, particularly for assessing the risk of intracranial haemorrhage. We aimed to develop new risk scores incorporating clinical variables and cerebral microbleeds, an MRI biomarker of intracranial haemorrhage and ischaemic stroke risk., Methods: We did a pooled analysis of individual-patient data from the Microbleeds International Collaborative Network (MICON), which includes 38 hospital-based prospective cohort studies from 18 countries. All studies recruited participants with previous ischaemic stroke or transient ischaemic attack, acquired baseline MRI allowing quantification of cerebral microbleeds, and followed-up participants for ischaemic stroke and intracranial haemorrhage. Participants not taking antithrombotic drugs were excluded. We developed Cox regression models to predict the 5-year risks of intracranial haemorrhage and ischaemic stroke, selecting candidate predictors on biological relevance and simplifying models using backward elimination. We derived integer risk scores for clinical use. We assessed model performance in internal validation, adjusted for optimism using bootstrapping. The study is registered on PROSPERO, CRD42016036602., Findings: The included studies recruited participants between Aug 28, 2001, and Feb 4, 2018. 15 766 participants had follow-up for intracranial haemorrhage, and 15 784 for ischaemic stroke. Over a median follow-up of 2 years, 184 intracranial haemorrhages and 1048 ischaemic strokes were reported. The risk models we developed included cerebral microbleed burden and simple clinical variables. Optimism-adjusted c indices were 0·73 (95% CI 0·69-0·77) with a calibration slope of 0·94 (0·81-1·06) for the intracranial haemorrhage model and 0·63 (0·62-0·65) with a calibration slope of 0·97 (0·87-1·07) for the ischaemic stroke model. There was good agreement between predicted and observed risk for both models., Interpretation: The MICON risk scores, incorporating clinical variables and cerebral microbleeds, offer predictive value for the long-term risks of intracranial haemorrhage and ischaemic stroke in patients prescribed antithrombotic therapy for secondary stroke prevention; external validation is warranted., Funding: British Heart Foundation and Stroke Association., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Abstract: Age-related sporadic cerebral small vessel disease (CSVD) has gained increasing attention over the past decades because of its increasing prevalence associated with an aging population. The widespread application of and advances in brain magnetic resonance imaging in recent decades have significantly increased researchers' understanding in the in vivo evolution of CSVD, its impact upon the brain, its risk factors, and the mechanisms that explain the various clinical manifestation associated with sporadic CSVD. In this review, we aimed to provide an update on the pathophysiology, risk factors, biomarkers, and the determinants and spectrum of the clinical manifestation of sporadic CSVD., (Copyright © 2020 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.)

We have provided an overview on the profound impact of COVID-19 upon older people with Alzheimer's disease and other dementias and the challenges encountered in our management of dementia in different health-care settings, including hospital, out-patient, care homes, and the community during the COVID-19 pandemic. We have also proposed a conceptual framework and practical suggestions for health-care providers in tackling these challenges, which can also apply to the care of older people in general, with or without other neurological diseases, such as stroke or parkinsonism. We believe this review will provide strategic directions and set standards for health-care leaders in dementia, including governmental bodies around the world in coordinating emergency response plans for protecting and caring for older people with dementia amid the COIVD-19 outbreak, which is likely to continue at varying severity in different regions around the world in the medium term., (© 2020 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: White matter hyperintensities (WMH) are associated with cognitive impairment. The impact of WMH on cognitive domains (e.g. processing speed, executive functioning) depends on location. We determined whether the relevance of WMH location also applies to global cognitive functioning by testing if WMH in strategic white matter tracts are associated with global cognitive functioning independent of total WMH burden., Methods: We included 830 community-dwelling individuals. WMH volume within two a priori specified strategic white matter tracts (forceps minor and anterior thalamic radiation) were entered in a linear regression model with the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE) as outcome variables and corrected for total WMH volume and other MRI markers for vascular injury and neurodegenerations (i.e. brain parenchymal fraction, and the presence of lacunes and microbleeds)., Results: WMH in the forceps minor and left anterior thalamic radiation inversely correlated with MoCA, and WMH in the forceps minor inversely correlated with MMSE, independent of total WMH volume and other MRI markers., Conclusion: The impact of WMH on global cognitive functioning depends on location. Whether this reflects accumulated impairment in isolated cognitive domains or disruption of a network that is crucially involved in global cognitive performance remains to be determined., Competing Interests: Declaration of Competing Interest The author(s) declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Microbleeds are a marker of cerebrovascular disease however its role in incident post-stroke dementia (PSD) remains unclear. We investigated whether microbleeds are associated with incident PSD, domain-specific cognitive impairment and cognitive decline over a 2-year follow-up; and whether microbleeds interact with acute stroke-related infarcts to synergistically affect cognitive outcomes. In a cohort of patients with first-episode mild ischemic stroke and no pre-stroke dementia, we found patients with 3 or more mixed microbleeds (presence of both lobar and deep) were 4 times more at risk of developing PSD compared to patients with no microbleeds. Patients with strictly lobar microbleeds were 10 times more at risk of developing memory impairment while patients with possible CAA-related microbleeds were 8 times more at risk of developing memory impairment compared to patients with no microbleeds. Microbleeds did not predict cognitive decline at the 2-year follow-up. Acute stroke infarcts were not related to any cognitive outcomes. Microbleeds did not interact with stroke infracts to synergistically affect cognitive outcomes. Our findings suggest that the combined effect of possible CAA and hypertension-related microbleeds play a large and direct role in incident PSD. Management of vasculopathy and amyloid deposition may positively impact cognitive outcomes after stroke., Competing Interests: Declaration of Competing Interest None to disclose., (Copyright © 2020. Published by Elsevier B.V.)

Background: The objective of this study is to examine the effects of recent regular participation leisure activities upon cognitive functions between 3 and 6 months after stroke or transient ischemic attack (TIA). We also explored whether the cognitive effects interacted with the severity of white matter hyperintensities (WMH), a marker of cerebral white matter disease, in patients with low or high education., Methods: Two-hundred and ninety-two subjects with mean age of 66.1 (11.0) years were recruited at median 161(131-180) days post index event. WMH volume was evaluated using a semi-automated method on MRI brain. Cognitive functions were measured using the Montreal Cognitive Assessment (MoCA). Multivariable linear regression analysis was conducted to explore the associations between leisure activity participation with WMH and the moderating effects of leisure activities upon relationship between WMH and MoCA. Analyses were further stratified by low (<6 years) or high education (≥6 years). All models were adjusted with age, sex, and years of education., Results: Physical activity (PA), but not intellectual activity (IA), was negatively related to WMH volume (P < .05). IA exerted a main effect on MoCA performance (b = 3.21, P < .001). PA, but not IA, significantly interacted with WMH volume (b = -0.18, P < .01) on MoCA performance, but the interaction was only significant in the lower education group (b = 0.28, P < .01) but not in the higher education group., Conclusions: In patients with stroke/TIA, IA confers general cognitive benefits. Regular participation in PA negatively correlated with WMH volume. In patients with low education, PA increases resilience against vascular cognitive impairment., (© 2019 John Wiley & Sons, Ltd.)

Objectives: Elderly persons harbouring severe white matter hyperintensity (WMH), a radiological manifestation of cerebral small vessel disease (SVD), have an increased risk of dementia, stroke and poor functional outcomes. A simple screening tool will enhance their recruitment into preventive trials for SVD. We explored the clinical utility of the pulsatility index (PI) of the middle cerebral artery (MCA), obtained from transcranial Doppler ultrasound (TCD), in identifying severe WMH among community elderly persons with vascular risk factors., Methods: Three hundred and thirty-one dementia- and stroke-free community elderly subjects with hypertension and/or diabetes mellitus underwent TCD to obtain the MCA PI. The WMH volume on 3.0 Tesla MRI was quantified and normalized to each subject's brain volume. The normalized WMH volumes were classified as low (<14.5 ml, 1 standard deviation [SD] above the mean, 84th percentile) or high (≥14.5 ml). The severity of WMH was also rated visually with the Fazekas score. Logistic regression and receiver-operator characteristics (ROC) analysis were performed to evaluate the association between the MCA PI and the severity of WMH., Results: The MCA PI was not an independent predictor of severe WMH. An MCA PI ≥1.095 detected high normalized WMH volumes with an area under the curve (AUC) of 0.553 (95% CI 0.473-0.633), sensitivity of 0.556, and specificity of 0.523. ROC analysis of the MCA PI in predicting high Fazekas scores yielded similar findings., Conclusion: In stroke- and dementia-free elderly persons with vascular risk factors, the MCA PI was unable to identify severe WMH. (Word count: 260)., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction: Only two studies investigated the associations between peak width of skeletonized mean diffusivity (PSMD) and age-related cognitive alterations, whereas none of the studies investigated the association with vascular risk factors., Methods: We evaluated 801 stroke- and dementia-free elderlies with baseline and 3-year follow-up assessments. Regression analyses were used to assess the association between age-related cognitive functions and PSMD. Simple mediation models were used to study the mediation effect of PSMD between vascular risk factors and age-related cognitive outcomes., Results: PSMD was negatively associated with processing speed at baseline and negatively associated with processing and memory scores at 3-year follow-up. The association between vascular risk factors and age-related cognition was mediated by PSMD, as well as other diffusion tensor imaging markers., Discussion: PSMD is preferred over other diffusion tensor imaging markers as it is sensitive to age-related cognitive alterations and calculation is fully automated. PSMD is proposed as a research tool to monitor age-related cognitive alterations., (© 2019 The Authors.)

Background: Cerebral microbleeds are a neuroimaging biomarker of stroke risk. A crucial clinical question is whether cerebral microbleeds indicate patients with recent ischaemic stroke or transient ischaemic attack in whom the rate of future intracranial haemorrhage is likely to exceed that of recurrent ischaemic stroke when treated with antithrombotic drugs. We therefore aimed to establish whether a large burden of cerebral microbleeds or particular anatomical patterns of cerebral microbleeds can identify ischaemic stroke or transient ischaemic attack patients at higher absolute risk of intracranial haemorrhage than ischaemic stroke., Methods: We did a pooled analysis of individual patient data from cohort studies in adults with recent ischaemic stroke or transient ischaemic attack. Cohorts were eligible for inclusion if they prospectively recruited adult participants with ischaemic stroke or transient ischaemic attack; included at least 50 participants; collected data on stroke events over at least 3 months follow-up; used an appropriate MRI sequence that is sensitive to magnetic susceptibility; and documented the number and anatomical distribution of cerebral microbleeds reliably using consensus criteria and validated scales. Our prespecified primary outcomes were a composite of any symptomatic intracranial haemorrhage or ischaemic stroke, symptomatic intracranial haemorrhage, and symptomatic ischaemic stroke. We registered this study with the PROSPERO international prospective register of systematic reviews, number CRD42016036602., Findings: Between Jan 1, 1996, and Dec 1, 2018, we identified 344 studies. After exclusions for ineligibility or declined requests for inclusion, 20 322 patients from 38 cohorts (over 35 225 patient-years of follow-up; median 1·34 years [IQR 0·19-2·44]) were included in our analyses. The adjusted hazard ratio [aHR] comparing patients with cerebral microbleeds to those without was 1·35 (95% CI 1·20-1·50) for the composite outcome of intracranial haemorrhage and ischaemic stroke; 2·45 (1·82-3·29) for intracranial haemorrhage and 1·23 (1·08-1·40) for ischaemic stroke. The aHR increased with increasing cerebral microbleed burden for intracranial haemorrhage but this effect was less marked for ischaemic stroke (for five or more cerebral microbleeds, aHR 4·55 [95% CI 3·08-6·72] for intracranial haemorrhage vs 1·47 [1·19-1·80] for ischaemic stroke; for ten or more cerebral microbleeds, aHR 5·52 [3·36-9·05] vs 1·43 [1·07-1·91]; and for ≥20 cerebral microbleeds, aHR 8·61 [4·69-15·81] vs 1·86 [1·23-1·82]). However, irrespective of cerebral microbleed anatomical distribution or burden, the rate of ischaemic stroke exceeded that of intracranial haemorrhage (for ten or more cerebral microbleeds, 64 ischaemic strokes [95% CI 48-84] per 1000 patient-years vs 27 intracranial haemorrhages [17-41] per 1000 patient-years; and for ≥20 cerebral microbleeds, 73 ischaemic strokes [46-108] per 1000 patient-years vs 39 intracranial haemorrhages [21-67] per 1000 patient-years)., Interpretation: In patients with recent ischaemic stroke or transient ischaemic attack, cerebral microbleeds are associated with a greater relative hazard (aHR) for subsequent intracranial haemorrhage than for ischaemic stroke, but the absolute risk of ischaemic stroke is higher than that of intracranial haemorrhage, regardless of cerebral microbleed presence, antomical distribution, or burden., Funding: British Heart Foundation and UK Stroke Association., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Introduction: The Meta VCI Map consortium performs meta-analyses on strategic lesion locations for vascular cognitive impairment using lesion-symptom mapping. Integration of data from different cohorts will increase sample sizes, to improve brain lesion coverage and support comprehensive lesion-symptom mapping studies., Methods: Cohorts with available imaging on white matter hyperintensities or infarcts and cognitive testing were invited. We performed a pilot study to test the feasibility of multicenter data processing and analysis and determine the benefits to lesion coverage., Results: Forty-seven groups have joined Meta VCI Map (stroke n = 7800 patients; memory clinic n = 4900; population-based n = 14,400). The pilot study (six ischemic stroke cohorts, n = 878) demonstrated feasibility of multicenter data integration (computed tomography/magnetic resonance imaging) and achieved marked improvement of lesion coverage., Discussion: Meta VCI Map will provide new insights into the relevance of vascular lesion location for cognitive dysfunction. After the successful pilot study, further projects are being prepared. Other investigators are welcome to join.

Background and Purpose: Cerebral microbleeds (CMBs), which predict future intracerebral haemorrhage (ICH), may guide anticoagulant decisions for atrial fibrillation (AF). We aimed to evaluate the risk of warfarin-associated ICH in Chinese patients with AF with CMBs., Methods: In this prospective, observational, multicentre study, we recruited Chinese patients with AF who were on or intended to start anticoagulation with warfarin from six hospitals in Hong Kong. CMBs were evaluated with 3T MRI brain at baseline. Primary outcome was clinical ICH at 2-year follow-up. Secondary outcomes were ischaemic stroke, systemic embolism, mortality of all causes and modified Rankin Scale ≥3. Outcome events were compared between patients with and without CMBs., Results: A total of 290 patients were recruited; 53 patients were excluded by predefined criteria. Among the 237 patients included in the final analysis, CMBs were observed in 84 (35.4%) patients, and 11 had ≥5 CMBs. The mean follow-up period was 22.4±10.3 months. Compared with patients without CMBs, patients with CMBs had numerically higher rate of ICH (3.6% vs 0.7%, p=0.129). The rate of ICH was lower than ischaemic stroke for patients with 0 to 4 CMBs, but higher for those with ≥5 CMBs. CMB count (C-index 0.82) was more sensitive than HAS-BLED (C-index 0.55) and CHA2DS2-VASc (C-index 0.63) scores in predicting ICH., Conclusions: In Chinese patients with AF on warfarin, presence of multiple CMBs may be associated with higher rate of ICH than ischaemic stroke. Larger studies through international collaboration are needed to determine the risk:benefit ratio of oral anticoagulants in patients with AF of different ethnic origins., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Many consequences of cerebrovascular disease are identifiable by magnetic resonance imaging (MRI), but variation in methods limits multicenter studies and pooling of data. The European Union Joint Program on Neurodegenerative Diseases (EU JPND) funded the HARmoNizing Brain Imaging MEthodS for VaScular Contributions to Neurodegeneration (HARNESS) initiative, with a focus on cerebral small vessel disease., Methods: Surveys, teleconferences, and an in-person workshop were used to identify gaps in knowledge and to develop tools for harmonizing imaging and analysis., Results: A framework for neuroimaging biomarker development was developed based on validating repeatability and reproducibility, biological principles, and feasibility of implementation. The status of current MRI biomarkers was reviewed. A website was created at www.harness-neuroimaging.org with acquisition protocols, a software database, rating scales and case report forms, and a deidentified MRI repository., Conclusions: The HARNESS initiative provides resources to reduce variability in measurement in MRI studies of cerebral small vessel disease.

Objectives: Individual neuroimaging features of small vessel disease (SVD) have been reported to influence poststroke cognition. This study aimed to investigate the joint contribution and strategic distribution patterns of multiple types of SVD imaging features in poststroke cognitive impairment., Methods: We studied 145 first-ever ischaemic stroke patients with MRI and Montreal Cognitive Assessment (MoCA) examined at baseline. The local burdens of acute ischaemic lesion (AIL), white matter hyperintensity, lacune, enlarged perivascular space and cross-sectional atrophy were quantified and entered into support vector regression (SVR) models to associate with the global and domain scores of MoCA. The SVR models were optimised with feature selection through 10-fold cross-validations. The contribution of SVD features to MoCA scores was measured by the prediction accuracy in the corresponding SVR model after optimisation., Results: The combination of the neuroimaging features of SVD contributed much more to the MoCA deficits on top of AILs compared with individual SVD features, and the cognitive impact of different individual SVD features was generally similar. As identified by the optimal SVR models, the important SVD-affected regions were mainly located in the basal ganglia and white matter around it, although the specific regions varied for MoCA and its domains., Conclusions: Multiple types of SVD neuroimaging features jointly had a significant impact on global and domain cognitive functionings after stroke on top of AILs. The map of strategic cognitive-relevant regions of SVD features may help clinicians to understand their complementary impact on poststroke cognition., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: The Montreal Cognitive Assessment (MoCA) is psychometrically superior over the Mini-mental State Examination (MMSE) for cognitive screening in stroke or transient ischemic attack (TIA). It is free for clinical and research use. The objective of this study is to convert scores from the MMSE to MoCA and MoCA-5-minute protocol (MoCA-5 min) and to examine the ability of the converted scores in detecting cognitive impairment after stroke or TIA., Methods: A total of 904 patients were randomly divided into training (n = 623) and validation (n = 281) samples matched for demography and cognition. MMSE scores were converted to MoCA and MoCA-5 min using (1) equipercentile method with log-linear smoothing and (2) Poisson regression adjusting for age and education. Receiver operating characteristics curve analysis was used to examine the ability of the converted scores in differentiating patients with cognitive impairment., Results: The mean education was 5.8 (SD = 4.6; ranged 0-20) years. The entire spectrum of MMSE scores was converted to MoCA and MoCA-5 min using equipercentile method. Relationship between MMSE and MoCA scores was confounded by age and education, and a conversion equation with adjustment for age and education was derived. In the validation sample, the converted scores differentiated cognitively impaired patients with area under receiver operating characteristics curve 0.826 to 0.859., Conclusion: We provided 2 methods to convert scores from the MMSE to MoCA and MoCA-5 min based on a large sample of patients with stroke or TIA having a wide range of education and cognitive levels. The converted scores differentiated patients with cognitive impairment after stroke or TIA with high accuracy., (Copyright © 2018 John Wiley & Sons, Ltd.)

Post-stroke cognitive impairment (PSCI) warrants early detection and management. We sought to develop a risk score for screening patients at bedside for risk of delayed PSCI. Ischemic stroke survivors with PSCI and no cognitive impairments (NCI) 3-6 months post-stroke were studied to identify candidate variables predictive of PSCI. These variables were used to develop a risk score using regression models. The score, and the best identified clinical cutoff point, underwent development, stability testing, and internal and external validation in three independent cohorts from Singapore and Hong Kong. Across 1,088 subjects, the risk score, dubbed CHANGE, had areas under the receiver operating characteristics curve (AUROC) from 0.74 to 0.82 in detecting significant risk for PSCI, and had predicted values following actual prevalence. In validation data 3-6 and 12-18 months post-stroke, subjects with low, medium, and high scores had PSCI prevalence of 7-23%, 25-58%, and 67-82%. CHANGE was effective in screening ischemic stroke survivors for significant risk of developing PSCI up to 18 months post-stroke. CHANGE used readily available and reliable clinical data, and may be useful in identifying at-risk patients for PSCI.

Introduction: Patients surviving stroke without immediate dementia are at high risk of delayed-onset dementia. Mechanisms underlying delayed-onset dementia are complex and may involve vascular and/or neurodegenerative diseases., Methods: Dementia-free patients with stroke and/or transient ischemic attack (TIA; n = 919) were studied for 3 years prospectively, excluding those who developed dementia 3 to 6 months after stroke and/or TIA., Results: Forty subjects (4.4%) developed dementia during the study period. Imaging markers of severe small vessel disease (SVD), namely presence of ≥3 lacunes and confluent white matter changes; history of hypertension and diabetes mellitus independently predicted delayed-onset dementia after adjustment for age, gender, and education. Only 6 of 31 (19.4%) subjects with delayed cognitive decline harbored Alzheimer's disease-like Pittsburg compound B (PiB) retention. Most PiB cases (16/25, 64%) had evidence of severe SVD., Discussion: Severe SVD contributes importantly to delayed-onset dementia after stroke and/or TIA. Future clinical trials aiming to prevent delayed-onset dementia after stroke and/or TIA should target this high-risk group., (Copyright © 2016 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)