SummaryCerebral small vessel disease (SVD) is a common accompaniment of ageing. Features seen on neuroimaging include recent small subcortical infarcts, lacunes, white matter hyperintensities, perivascular spaces, microbleeds, and brain atrophy. SVD can present as a stroke or cognitive decline, or can have few or no symptoms. SVD frequently coexists with neurodegenerative disease, and can exacerbate cognitive deficits, physical disabilities, and other symptoms of neurodegeneration. Terminology and definitions for imaging the features of SVD vary widely, which is also true for protocols for image acquisition and image analysis. This lack of consistency hampers progress in identifying the contribution of SVD to the pathophysiology and clinical features of common neurodegenerative diseases. We are an international working group from the Centres of Excellence in Neurodegeneration. We completed a structured process to develop definitions and imaging standards for markers and consequences of SVD. We aimed to achieve the following: first, to provide a common advisory about terms and definitions for features visible on MRI; second, to suggest minimum standards for image acquisition and analysis; third, to agree on standards for scientific reporting of changes related to SVD on neuroimaging; and fourth, to review emerging imaging methods for detection and quantification of preclinical manifestations of SVD. Our findings and recommendations apply to research studies, and can be used in the clinical setting to standardise image interpretation, acquisition, and reporting. This Position Paper summarises the main outcomes of this international effort to provide the STandards for ReportIng Vascular changes on nEuroimaging (STRIVE).

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IMPORTANCE Large-scale genome-wide association studies in the European population have identified 90 risk variants associated with Parkinson disease (PD); however, there are limited studies in the largest population worldwide (ie, Asian).OBJECTIVES To identify novel genome-wide significant loci for PD in Asian individuals and to compare genetic risk between Asian and European cohorts.DESIGN SETTING, AND PARTICIPANTS Genome-wide association data generated from PD cases and controls in an Asian population (ie, Singapore/Malaysia, Hong Kong, Taiwan, mainland China, and South Korea) were collected from January 1, 2016, to December 31, 2018, as part of an ongoing study. Results were combined with inverse variance meta-analysis, and replication of top loci in European and Japanese samples was performed. Discovery samples of 31 575 individuals passing quality control of 35 994 recruited were used, with a greater than 90% participation rate. A replication cohort of 1 926 361 European-ancestry and 3509 Japanese samples was analyzed. Parkinson disease was diagnosed using UK Parkinson's Disease Society Brain Bank Criteria. MAIN OUTCOMES AND MEASURESGenotypes of common variants, association with disease status, and polygenic risk scores. RESULTS Of 31 575 samples identified, 6724 PD cases (mean [SD] age, 64.3 [10] years; age at onset, 58.8 [10.6] years; 3472 [53.2%] men) and 24 851 controls (age, 59.4 [11.4] years; 11 030 [45.0%] men) were analyzed in the discovery study. Eleven genome-wide significant loci were identified; 2 of these loci were novel (SV2C and WBSCR17) and 9 were previously found in Europeans. Replication in European-ancestry and Japanese samples showed robust association for SV2C (rs246814; odds ratio, 1.16; 95% CI, 1.11-1.21; P = 1.17 × 10 −10 in metaanalysis of discovery and replication samples) but showed potential genetic heterogeneity at WBSCR17 (rs9638616; I 2 =67.1%; P = 3.40 × 10 −3 for hetereogeneity). Polygenic risk score models including variants at these 11 loci were associated with a significant improvement in area under the curve over the model based on 78 European loci alone (63.1% vs 60.2%; P = 6. 81 × 10 −12 ).CONCLUSIONS AND RELEVANCE This study identified 2 apparently novel gene loci and found 9 previously identified European loci to be associated with PD in this large, meta-genome-wide association study in a worldwide population of Asian individuals and reports similarities and differences in genetic risk factors between Asian and European individuals in the risk for PD. These findings may lead to improved stratification of Asian patients and controls based on polygenic risk scores. Our findings have potential academic and clinical importance for risk stratification and precision medicine in Asia.

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.

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Age-related white matter changes (WMC) are considered manifestation of arteriolosclerotic small vessel disease and are related to age and vascular risk factors. Most recent studies have shown that WMC are associated with a host of poor outcomes, including cognitive impairment, dementia, urinary incontinence, gait disturbances, depression, and increased risk of stroke and death. Although the clinical relevance of WMC has been extensively studied, to date, only very few clinical trials have evaluated potential symptomatic or preventive treatments for WMC. In this paper, we reviewed the current understanding in the pathophysiology, epidemiology, clinical importance, chemical biomarkers, and treatments of age-related WMC.

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.