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Introduction: Prasinezumab was shown to potentially delay motor progression in individuals with early-stage Parkinson's disease (PD) who were either treatment-naïve or on monoamine oxidase type B inhibitor (MAO-Bi) therapy in the PASADENA study. We report the rationale, design, and baseline patient characteristics of the PADOVA study, designed to evaluate prasinezumab in an early-stage PD population receiving standard-of-care (SOC) symptomatic medications., Methods: PADOVA (NCT04777331) is a Phase 2b, multicenter, randomized, double-blind, placebo-controlled, parallel-group study, in which individuals with early-stage PD on SOC stable symptomatic monotherapy (levodopa or MAO-Bi) receive intravenous prasinezumab 1500 mg every 4 weeks. The primary endpoint is time to confirmed motor progression, defined as ≥5 points increase from baseline on the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III in practically defined OFF-medication state., Results: 586 participants were enrolled between May 5th, 2021 and March 22nd, 2023. At baseline, 74.2 % and 25.8 % of participants were receiving levodopa and MAO-Bi, respectively. Mean age was 64.2 years and 63.5 % were male. Mean time from diagnosis was 18.6 months, 85 % of participants were in Hoehn & Yahr (H&Y) Stage 2, and mean MDS-UPDRS Part III score was 24.5. Compared with the PASADENA population, PADOVA participants were older (∼5 years), with longer disease duration (∼8 months), and slightly more advanced based on H&Y stage (10 % more in Stage 2) and MDS-UPDRS Part III (∼3 points more)., Conclusions: PADOVA has successfully recruited an early-stage PD population to test the effect of prasinezumab when added to background SOC., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Tania Nikolcheva reports financial support was provided by F Hoffmann-La Roche Ltd. Tania Nikolcheva reports a relationship with F Hoffmann-La Roche Ltd that includes: employment and equity or stocks. Gennaro Pagano reports a relationship with F Hoffmann-La Roche Ltd that includes: employment and equity or stocks. Nathalie Pross reports a relationship with F Hoffmann-La Roche Ltd that includes: employment and equity or stocks. Gesine Respondek reports a relationship with F Hoffmann-La Roche Ltd that includes: employment and equity or stocks. Annabelle Monnet reports a relationship with F Hoffmann-La Roche Ltd that includes: employment and equity or stocks. Nima Shariati reports a relationship with F Hoffmann-La Roche Ltd that includes: employment and equity or stocks. Benedicte Ricci reports a relationship with F Hoffmann-La Roche Ltd that includes: employment and equity or stocks. Loes Rutten-Jacobs reports a relationship with F Hoffmann-La Roche Ltd that includes: employment and equity or stocks. Thomas Kustermann reports a relationship with F Hoffmann-La Roche Ltd that includes: employment and equity or stocks. Kirsten I. Taylor reports a relationship with F Hoffmann-La Roche Ltd that includes: employment and equity or stocks. Azad Bonni reports a relationship with F Hoffmann-La Roche Ltd that includes: employment and equity or stocks. Dylan Trundell reports a relationship with F Hoffmann-La Roche Ltd that includes: equity or stocks. Dylan Trundell reports a relationship with Roche Products Ltd that includes: employment. Hanno Svoboda reports a relationship with F Hoffmann-La Roche Ltd that includes: employment and equity or stocks. Tanya Simuni reports a relationship with Acurex that includes: board membership and consulting or advisory. Tanya Simuni reports a relationship with Adamas that includes: board membership and consulting or advisory. Tanya Simuni reports a relationship with AskBio that includes: board membership and consulting or advisory. Tanya Simuni reports a relationship with Amneal that includes: consulting or advisory and funding grants. Tanya Simuni reports a relationship with Blue Rock Therapeutics that includes: consulting or advisory. Tanya Simuni reports a relationship with Critical Path for Parkinson's Consortium that includes: consulting or advisory. Tanya Simuni reports a relationship with Denali that includes: board membership and consulting or advisory. Tanya Simuni reports a relationship with The Michael J Fox Foundation that includes: consulting or advisory. Tanya Simuni reports a relationship with NeuroDerm Ltd that includes: board membership, consulting or advisory, and funding grants. Tanya Simuni reports a relationship with Sanofi that includes: board membership and consulting or advisory. Tanya Simuni reports a relationship with Sinopia that includes: consulting or advisory. Tanya Simuni reports a relationship with Roche that includes: board membership, consulting or advisory, and funding grants. Tanya Simuni reports a relationship with Takeda that includes: consulting or advisory. Tanya Simuni reports a relationship with Vanqua Bio, Inc. that includes: consulting or advisory. Tanya Simuni reports a relationship with UCB that includes: board membership and funding grants. Tanya Simuni reports a relationship with Biogen that includes: funding grants. Tanya Simuni reports a relationship with Prevail Therapeutics that includes: funding grants. Tanya Simuni reports a relationship with National Institute of Neurological Disorders and Stroke that includes: consulting or advisory. Tanya Simuni reports a relationship with Parkinson's Foundation that includes: consulting or advisory. Kenneth Marek reports a relationship with Michael J Fox Foundation for Parkinson's Research that includes: consulting or advisory. Kenneth Marek reports a relationship with F Hoffmann-La Roche Ltd that includes: consulting or advisory. Kenneth Marek reports a relationship with UCB that includes: consulting or advisory. Kenneth Marek reports a relationship with Denali that includes: consulting or advisory. Kenneth Marek reports a relationship with Takeda that includes: consulting or advisory. Kenneth Marek reports a relationship with Biohaven Ltd that includes: consulting or advisory. Kenneth Marek reports a relationship with Neuron23 that includes: consulting or advisory. Kenneth Marek reports a relationship with Aprinoia that includes: consulting or advisory. Kenneth Marek reports a relationship with Prothena that includes: consulting or advisory. Kenneth Marek reports a relationship with Calico that includes: consulting or advisory. Kenneth Marek reports a relationship with Inhibikase that includes: consulting or advisory. Kenneth Marek reports a relationship with Invicro that includes: consulting or advisory. Kenneth Marek reports a relationship with Koneksa that includes: consulting or advisory. Kenneth Marek reports a relationship with Lilly that includes: consulting or advisory. Ronald B. Postuma reports a relationship with Fonds de la Recherche en Sante that includes: funding grants. Ronald B. Postuma reports a relationship with Canadian Institutes of Health Research that includes: funding grants. Ronald B. Postuma reports a relationship with The Michael J Fox Foundation that includes: funding grants. Ronald B. Postuma reports a relationship with Webster Foundation that includes: funding grants. Ronald B. Postuma reports a relationship with Roche that includes: funding grants. Ronald B. Postuma reports a relationship with National Institutes of Health that includes: funding grants. Ronald B. Postuma reports a relationship with Takeda that includes: funding grants. Ronald B. Postuma reports a relationship with Biogen that includes: funding grants. Ronald B. Postuma reports a relationship with Abbvie that includes: funding grants. Ronald B. Postuma reports a relationship with Curasen that includes: funding grants. Ronald B. Postuma reports a relationship with Lilly that includes: funding grants. Ronald B. Postuma reports a relationship with Novartis that includes: funding grants. Ronald B. Postuma reports a relationship with Eisai that includes: funding grants. Ronald B. Postuma reports a relationship with Paladin that includes: funding grants. Ronald B. Postuma reports a relationship with Merck that includes: funding grants. Ronald B. Postuma reports a relationship with Vaxxinity that includes: funding grants. Ronald B. Postuma reports a relationship with Korro that includes: funding grants. Ronald B. Postuma reports a relationship with Bristol Myers Squibb that includes: funding grants. Ronald B. Postuma reports a relationship with International Parkinson and Movement Disorder Society that includes: board membership and funding grants. Nicola Pavese reports a relationship with Britannia that includes: board membership and funding grants. Nicola Pavese reports a relationship with Boston Scientific that includes: board membership and funding grants. Nicola Pavese reports a relationship with Benevolent AI that includes: board membership. Nicola Pavese reports a relationship with F Hoffmann-La Roche inc that includes: board membership. Nicola Pavese reports a relationship with AbbVie Inc that includes: board membership and funding grants. Nicola Pavese reports a relationship with GE Healthcare that includes: funding grants. Nicola Pavese reports a relationship with Independent Research Fund Denmark that includes: funding grants. Nicola Pavese reports a relationship with Danish Parkinson's Disease Association that includes: funding grants. Nicola Pavese reports a relationship with Parkinson's UK that includes: funding grants. Nicola Pavese reports a relationship with Center of Excellence in Neurodegeneration network award that includes: funding grants. Nicola Pavese reports a relationship with GE Healthcare Grant that includes: funding grants. Nicola Pavese reports a relationship with Multiple System Atrophy Trust that includes: funding grants. Nicola Pavese reports a relationship with Weston Brain Institute that includes: funding grants. Nicola Pavese reports a relationship with EU Joint Programme Neurodegenerative Disease Research that includes: funding grants. Nicola Pavese reports a relationship with EU Horizon 2020 research that includes: funding grants. Nicola Pavese reports a relationship with The Michael J Fox Foundation for Parkinson's Research that includes: funding grants. Nicola Pavese reports a relationship with F Hoffmann-La Roche Ltd that includes: funding grants. Fabrizio Stocchi reports a relationship with AbbVie that includes: consulting or advisory. Fabrizio Stocchi reports a relationship with Bial Pharma that includes: consulting or advisory. Fabrizio Stocchi reports a relationship with Biogen Inc that includes: consulting or advisory. Fabrizio Stocchi reports a relationship with F Hoffmann-La Roche Ltd that includes: consulting or advisory. Fabrizio Stocchi reports a relationship with H. Lundbeck A S that includes: consulting or advisory. Fabrizio Stocchi reports a relationship with Mitsubishi Tanabe Pharma America Inc that includes: consulting or advisory. Fabrizio Stocchi reports a relationship with Sunovion Pharmaceuticals Inc that includes: consulting or advisory. Fabrizio Stocchi reports a relationship with Teva Pharmaceutical Industries that includes: consulting or advisory. Fabrizio Stocchi reports a relationship with Zambon that includes: consulting or advisory. Fabrizio Stocchi reports a relationship with Britannia that includes: consulting or advisory. Klaus Seppi reports a relationship with FWF Austrian Science Fund that includes: funding grants. Klaus Seppi reports a relationship with The Michael J Fox Foundation that includes: funding grants. Klaus Seppi reports a relationship with International Parkinson and Movement Disorder Society that includes: funding grants. Klaus Seppi reports a relationship with AOP Orphan Pharmaceuticals AG that includes: funding grants. Klaus Seppi reports a relationship with EU (all to the institution) that includes: funding grants. Klaus Seppi reports a relationship with Ono Pharma UK Ltd that includes: consulting or advisory. Klaus Seppi reports a relationship with Lundbeck that includes: consulting or advisory. Klaus Seppi reports a relationship with Ever Pharma that includes: consulting or advisory. Klaus Seppi reports a relationship with Teva that includes: speaking and lecture fees. Klaus Seppi reports a relationship with UCB that includes: speaking and lecture fees. Klaus Seppi reports a relationship with AOP Orphan Pharmaceuticals AG that includes: speaking and lecture fees. Klaus Seppi reports a relationship with Roche that includes: speaking and lecture fees. Klaus Seppi reports a relationship with Grünenthal that includes: speaking and lecture fees. Klaus Seppi reports a relationship with Stada that includes: speaking and lecture fees. Klaus Seppi reports a relationship with Licher Pharma that includes: speaking and lecture fees. Klaus Seppi reports a relationship with Biogen that includes: speaking and lecture fees. Klaus Seppi reports a relationship with Bial that includes: consulting or advisory and speaking and lecture fees. Klaus Seppi reports a relationship with AbbVie that includes: consulting or advisory and speaking and lecture fees. Klaus Seppi reports a relationship with Stada that includes: consulting or advisory. Paulo Fontoura reports a relationship with F Hoffmann-La Roche Ltd that includes: equity or stocks, and relationships with Harness Therapeutics and Stalicla SA that includes: employment, equity or stocks, and a relationship with Xaira Therapeutics that includes: employment, equity or stocks. Rachelle Doody reports a relationship with F Hoffmann-La Roche Ltd that includes: past employment, current stock and stock options. If there are other authors, they 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 © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: This retrospective real-world study used data from two registries, International Pediatric Peritoneal Dialysis Network (IPPN) and International Pediatric Hemodialysis Network (IPHN), to characterize the efficacy and safety of continuous erythropoietin receptor activator (C.E.R.A.) in pediatric patients with chronic kidney disease (CKD) on peritoneal dialysis (PD) or hemodialysis (HD)., Methods: IPPN and IPHN collect prospective data (baseline and every 6 months) from pediatric PD and HD centers worldwide. Demographics, clinical characteristics, dialysis information, treatment, laboratory parameters, number and causes of hospitalization events, and deaths were extracted for patients on C.E.R.A. treatment (IPPN: 2007-2021; IPHN: 2013-2021)., Results: We analyzed 177 patients on PD (median age 10.6 years) and 52 patients on HD (median age 14.1 years) who had ≥ 1 observation while being treated with C.E.R.A. The median (interquartile range [IQR]) observation time under C.E.R.A. exposure was 6 (0-12.5) and 12 (0-18) months, respectively. Hemoglobin concentrations were stable over time; respective means (standard deviation) at last observation were 10.9 (1.7) g/dL and 10.4 (1.7) g/dL. Respective median (IQR) monthly C.E.R.A. doses at last observation were 3.5 (2.3-5.1) µg/kg, or 95 (62-145) µg/m 2 and 2.1 (1.2-3.4) µg/kg, or 63 (40-98) µg/m 2 . Non-elective hospitalizations occurred in 102 (58%) PD and 32 (62%) HD patients. Seven deaths occurred (19.8 deaths per 1000 observation years)., Conclusions: C.E.R.A. was associated with efficient maintenance of hemoglobin concentrations in pediatric patients with CKD on dialysis, and appeared to have a favorable safety profile. The current analysis revealed no safety signals., (© 2023. The Author(s).)

Background: Despite efforts to increase diversity in neuroscience trials, racial and ethnic minority groups remain underrepresented. Disparities in clinical trial participation could reflect unequal opportunities to participate and may contribute to decreased generalizability of findings and failure to identify important differences in efficacy and safety outcomes., Methods: We retrospectively reviewed the F. Hoffmann-La Roche database for global, multicenter, neuroscience clinical trials from February 2016 to February 2021 and summarized and stratified race and ethnicity distributions by clinical trial therapeutic area and by country. These data were then compared to national population data for each study's targeted age group (available for studies conducted in the US, Canada, and the UK). The underrepresentation or overrepresentation of each racial and ethnic group was summarized., Results: The analysis population included 8015 participants from 47 countries. Globally, 85.6 % of participants were White, 7.1 % were Asian, 1.6 % were Black, 1.3 % were American Indian or Alaska Native, less than 0.1 % were Native Hawaiian or other Pacific Islander, 0.7 % were of multiple races, and 3.6 % were of other/unknown race. White individuals predominated in all but one trial. Black individuals were underrepresented in all trials but one. Asian individuals were overrepresented in approximately 20 % of trials. In the US, 7.3 % of participants were of Hispanic or Latino ethnicity vs 16.4 % of the US population., Conclusion: The findings and learnings from this summary and analysis demonstrate the need for continued awareness and new approaches in designing studies that reflect population diversity., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: LR-J, AR, MP, RR, CTP, and KRW are employees of and may own stock or stock options in F. Hoffmann-La Roche Ltd. TM is an employee of and may own stock or stock options in Roche Products Ltd. RD is an employee of and may own stock or stock options in F. Hoffmann-La Roche Ltd and Genentech, a Member of the Roche Group., (© 2024 The Authors. Published by Elsevier Inc.)

Background: Huntington's disease (HD) is a rare neurodegenerative disease that presents with progressive psychological, cognitive and motor impairment. These diverse symptoms place a high burden on the patient, families and the healthcare systems they rely on. This study aimed to describe the epidemiology and clinical burden in individuals with HD compared with controls from the general population., Methods: This cohort study utilised data from general practitioner medical records to estimate the prevalence and incidence of HD between January 2000 and December 2018. A cohort of incident HD cases were matched 1:3 to controls from the general population, in whom common clinical diagnoses, medications and healthcare interventions were compared at the time of first recorded diagnosis and at a time close to death. Incidence rates of common diagnoses and mortality were compared with matched controls in the time following HD diagnosis., Results: Prevalence of HD increased between 2000 and 2018, whilst incidence remained stable. Prevalence of psychiatric diagnoses and symptomatic treatments were higher in HD cases than controls. A higher relative risk of psychotic disorders, depression, insomnia, dementia, weight loss, pneumonia and falls was observed in HD cases. Risk of death was >4 times higher in HD, with a median survival of ~12 years from first recorded diagnosis., Conclusions: This study demonstrates the significant and progressive clinical burden in individuals with HD up to 18 years after first recorded diagnosis., (© 2022 F. Hoffmann La Roche. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Quality of life and health utility are important outcomes for patients with Alzheimer's disease (AD) and central for demonstrating the value of new treatments. Estimates in biomarker-confirmed AD populations are missing, potentially delaying payer approval of treatment. We examined whether health utility, assessed with the EuroQoL-5 3-level version (EQ-5D-3L), differed between individuals with a positive or negative amyloid beta (Aβ) biomarker in patients with mild cognitive impairment (MCI) and cognitively unimpaired (CU) participants from the Swedish BioFINDER study (n = 578). Participants with prodromal AD (Aβ-positive MCI) reported better health utility (n = 79, mean = 0.81, 95% confidence interval [CI] 0.77-0.85) than Aβ-negative MCI (mean = 0.71, 95% CI 0.64-0.78), but worse than controls (Aβ-negative CU, mean = 0.87, 95% CI 0.86-0.89). Health utility in preclinical AD (Aβ-positive CU; mean = 0.86, 95% CI 0.83-0.89) was similar to controls. This relatively good health utility in prodromal AD suggests a larger value of delaying progression to dementia than previously anticipated and a great value of delaying clinical progression in preclinical AD., (© 2021 the Alzheimer's Association.)

Early prediction of risk of cardiovascular disease (CVD), including stroke, is a cornerstone of disease prevention. Clinical risk scores have been widely used for predicting CVD risk from known risk factors. Most CVDs have a substantial genetic component, which also has been confirmed for stroke in recent gene discovery efforts. However, the role of genetics in prediction of risk of CVD, including stroke, has been limited to testing for highly penetrant monogenic disorders. In contrast, the importance of polygenic variation, the aggregated effect of many common genetic variants across the genome with individually small effects, has become more apparent in the last 5 to 10 years, and powerful polygenic risk scores for CVD have been developed. Here we review the current state of the field of polygenic risk scores for CVD including stroke, and their potential to improve CVD risk prediction. We present findings and lessons from diseases such as coronary artery disease as these will likely be useful to inform future research in stroke polygenic risk prediction.

Background: The genetic basis of lacunar stroke is poorly understood, with a single locus on 16q24 identified to date. We sought to identify novel associations and provide mechanistic insights into the disease., Methods: We did a pooled analysis of data from newly recruited patients with an MRI-confirmed diagnosis of lacunar stroke and existing genome-wide association studies (GWAS). Patients were recruited from hospitals in the UK as part of the UK DNA Lacunar Stroke studies 1 and 2 and from collaborators within the International Stroke Genetics Consortium. Cases and controls were stratified by ancestry and two meta-analyses were done: a European ancestry analysis, and a transethnic analysis that included all ancestry groups. We also did a multi-trait analysis of GWAS, in a joint analysis with a study of cerebral white matter hyperintensities (an aetiologically related radiological trait), to find additional genetic associations. We did a transcriptome-wide association study (TWAS) to detect genes for which expression is associated with lacunar stroke; identified significantly enriched pathways using multi-marker analysis of genomic annotation; and evaluated cardiovascular risk factors causally associated with the disease using mendelian randomisation., Findings: Our meta-analysis comprised studies from Europe, the USA, and Australia, including 7338 cases and 254 798 controls, of which 2987 cases (matched with 29 540 controls) were confirmed using MRI. Five loci (ICA1L-WDR12-CARF-NBEAL1, ULK4, SPI1-SLC39A13-PSMC3-RAPSN, ZCCHC14, ZBTB14-EPB41L3) were found to be associated with lacunar stroke in the European or transethnic meta-analyses. A further seven loci (SLC25A44-PMF1-BGLAP, LOX-ZNF474-LOC100505841, FOXF2-FOXQ1, VTA1-GPR126, SH3PXD2A, HTRA1-ARMS2, COL4A2) were found to be associated in the multi-trait analysis with cerebral white matter hyperintensities (n=42 310). Two of the identified loci contain genes (COL4A2 and HTRA1) that are involved in monogenic lacunar stroke. The TWAS identified associations between the expression of six genes (SCL25A44, ULK4, CARF, FAM117B, ICA1L, NBEAL1) and lacunar stroke. Pathway analyses implicated disruption of the extracellular matrix, phosphatidylinositol 5 phosphate binding, and roundabout binding (false discovery rate <0·05). Mendelian randomisation analyses identified positive associations of elevated blood pressure, history of smoking, and type 2 diabetes with lacunar stroke., Interpretation: Lacunar stroke has a substantial heritable component, with 12 loci now identified that could represent future treatment targets. These loci provide insights into lacunar stroke pathogenesis, highlighting disruption of the vascular extracellular matrix (COL4A2, LOX, SH3PXD2A, GPR126, HTRA1), pericyte differentiation (FOXF2, GPR126), TGF-β signalling (HTRA1), and myelination (ULK4, GPR126) in disease risk., Funding: British Heart Foundation., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objective: To identify novel genetic associations with white matter hyperintensities (WMH)., Methods: We performed a genome-wide association meta-analysis of WMH volumes in 11,226 individuals, including 8,429 population-based individuals from UK Biobank and 2,797 stroke patients. Replication of novel loci was performed in an independent dataset of 1,202 individuals. In all studies, WMH were quantified using validated automated or semi-automated methods. Imputation was to either the Haplotype Reference Consortium or 1,000 Genomes Phase 3 panels., Results: We identified a locus at genome-wide significance in an intron of PLEKHG1 (rs275350, β [SE] = 0.071 [0.013]; p = 1.6 × 10 -8 ), a Rho guanine nucleotide exchange factor that is involved in reorientation of cells in the vascular endothelium. This association was validated in an independent sample (overall p value, 2.4 × 10 -9 ). The same single nucleotide polymorphism was associated with all ischemic stroke (odds ratio [OR] [95% confidence interval (CI)] 1.07 [1.03-1.12], p = 0.00051), most strongly with the small vessel subtype (OR [95% CI] 1.09 [1.00-1.19], p = 0.044). Previous associations at 17q25 and 2p16 reached genome-wide significance in this analysis (rs3744020; β [SE] = 0.106 [0.016]; p = 1.2 × 10 -11 and rs7596872; β [SE] = 0.143 [0.021]; p = 3.4 × 10 -12 ). All identified associations with WMH to date explained 1.16% of the trait variance in UK Biobank, equivalent to 6.4% of the narrow-sense heritability., Conclusions: Genetic variation in PLEKHG1 is associated with WMH and ischemic stroke, most strongly with the small vessel subtype, suggesting it acts by promoting small vessel arteriopathy., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background and Purpose: The relationship between type 2 diabetes mellitus (T2D) and cerebral small vessel disease (CSVD) is unclear. We aimed to examine the causal effect of T2D, fasting glucose levels, and higher insulin resistance on CSVD using Mendelian randomization., Methods: Five CSVD phenotypes were studied; 2 were clinical outcomes associated with CSVD (lacunar stroke: n=2191/27 297 and intracerebral hemorrhage [ICH]: n=2254/8195 [deep and lobar ICH]), whereas 3 were radiological markers of CSVD (white matter hyperintensities: n=8429; fractional anisotropy [FA]: n=8357; and mean diffusivity: n=8357). We applied 2 complementary analyses to evaluate the association of T2D with CSVD. First, we used summarized data from genome-wide association study to calculate the effects of T2D-related variants on CSVD with inverse-variance weighted and weighted median approaches. Second, we performed a genetic risk score approach to test the effects of T2D-associated variants on white matter hyperintensities, FA, and mean diffusivity using individual-level data in UK Biobank., Results: T2D was associated with higher risk of lacunar stroke (odds ratio [OR], 1.15; 95% confidence interval [CI], 1.04-1.28; P =0.007) and lower mean FA (OR, 0.78; 95% CI, 0.66-0.92; P =0.004) but not white matter hyperintensities volume (OR, 1.01; 95% CI, 0.97-1.04; P =0.626), higher mean diffusivity (OR, 1.04; 95% CI, 0.89-1.23; P =0.612), ICH (OR, 1.07; 95% CI, 0.95-1.20; P =0.269), lobar ICH (OR, 1.07; 95% CI, 0.89-1.28; P =0.466), or deep ICH (OR, 1.16; 95% CI, 0.99-1.36; P =0.074). Weighted median and penalized median weighted analysis showed similar effect estimates of T2D on lacunar stroke and FA, but with wider CIs, meaning they were not significant. The genetic score on individual-level data was significantly associated with FA (OR, 0.63; 95% CI, 0.45-0.89; P =0.008) after adjusting for potential confounders., Conclusions: Our Mendelian randomization study provides evidence to suggest that T2D may be causally associated with CSVD, in particular with lacunar stroke and FA., (© 2018 The Authors.)

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.

Cerebral small vessel disease (SVD) is a common cause of lacunar strokes, vascular cognitive impairment (VCI) and vascular dementia. SVD is thought to result in reduced cerebral blood flow, impaired cerebral autoregulation and increased blood-brain barrier (BBB) permeability. However, the molecular mechanisms underlying SVD are incompletely understood. Recent studies in monogenic forms of SVD, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and 'sporadic' SVD have shed light on possible disease mechanisms in SVD. Proteomic and biochemical studies in post-mortem monogenic SVD patients, as well as in animal models of monogenic disease have suggested that disease pathways are shared between different types of monogenic disease, often involving the impairment of extracellular matrix (ECM) function. In addition, genetic studies in 'sporadic' SVD have also shown that the disease is highly heritable, particularly among young-onset stroke patients, and that common variants in monogenic disease genes may contribute to disease processes in some SVD subtypes. Genetic studies in sporadic lacunar stroke patients have also suggested distinct genetic mechanisms between subtypes of SVD. Genome-wide association studies (GWAS) have also shed light on other potential disease mechanisms that may be shared with other diseases involving the white matter, or with pathways implicated in monogenic disease. This review brings together recent data from studies in monogenic SVD and genetic studies in 'sporadic' SVD. It aims to show how these provide new insights into the pathogenesis of SVD, and highlights the possible convergence of disease mechanisms in monogenic and sporadic SVD., (© 2017 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.)

Objective: Despite epidemiologic data showing an increased stroke incidence in African ancestry populations, genetic studies in this group have so far been limited, and there has been little characterization of the genetic contribution to stroke liability in this population, particularly for stroke subtypes., Methods: We evaluated the evidence that genetic factors contribute to stroke and stroke subtypes in a population of 917 African and African Caribbean stroke cases and 868 matched controls from London, United Kingdom. We (1) estimated the heritability of stroke in this population using genomic-relatedness matrix-restricted maximum likelihood approaches, (2) assessed loci associated with stroke in Europeans in our population, and (3) evaluated the influence of genetic factors underlying cardiovascular risk factors on stroke using polygenic risk scoring., Results: Our results indicate a substantial genetic contribution to stroke risk in African ancestry populations (h 2 = 0.35 [SE = 0.19], p = 0.043). Polygenic risk scores indicate that cardiovascular risk scores contribute to the genetic liability (odds ratio [OR] 1.09 [95% confidence interval (CI) 1.01-1.17], p = 0.029) and point to a strong influence of type 2 diabetes in large vessel stroke (OR 1.62 [95% CI 1.19-2.22], p = 0.0024). Single nucleotide polymorphisms associated with ischemic stroke in Europeans shared direction of effect in SLESS ( p = 0.031), suggesting that disease mechanisms are shared across ancestries., Conclusions: Stroke in African ancestry populations is highly heritable and influenced by genetic determinants underlying cardiovascular risk factors. In addition, stroke loci identified in Europeans share direction of effect in African populations. Future genome-wide association studies must focus on incorporating African ancestry individuals.

Background and Purpose: Few studies exist on long-term post-stroke depressive symptoms and anxiety in young adults, although these young patients have a particular interest in their long-term prognosis, given their usually long life expectancy and being in the midst of an active social, working and family life. The aims of this study were to investigate the prevalence of depressive symptoms and anxiety and their association with clinical and demographic variables and with functional outcome after stroke in young adults., Methods and Results: Long-term prevalence of depressive symptoms and anxiety was calculated in 511 patients with a transient ischaemic attack or ischaemic stroke, aged 18-50 years, using the Hospital Anxiety and Depression scale, compared with 147 controls. Functional outcome was assessed with the modified Rankin Score (mRS) and the Instrumental Activities of Daily Living scale (IADL). 16.8% of patients had depressive symptoms and 23.0% had anxiety, versus 6.1% (P = 0.001) and 12.2% (P < 0.001) in controls. In ischaemic stroke patients, depressive symptoms and anxiety were associated with poor functional outcome (mRS > 2 or IADL < 8)., Conclusion: Even a decade after stroke at young age, depressive symptoms and anxiety were prevalent and associated with poor functional outcome. Therefore, even in the long term, treating physicians should be aware of the long-term presence of these symptoms as their recognition may be the first step in improving long-term functional independence., (© 2016 EAN.)

Introduction: Cerebral small vessel disease is one of the most important risk factors for dementia, and has been related to hippocampal atrophy, which is among the first observed changes on conventional MRI in patients with dementia. However, these volumetric changes might be preceded by loss of microstructural integrity of the hippocampus for which conventional MRI is not sensitive enough. Therefore, we investigated the relation between the hippocampal diffusion parameters and the risk of incident dementia, using diffusion tensor imaging, independent of hippocampal volume., Methods: The RUNDMC study is a prospective study among 503 elderly with small vessel disease, without dementia, with 5 years follow-up in 2012 (99.6% response-rate). Cox regression analysis was performed to calculate hazard ratios for dementia, of fractional anisotropy and mean diffusivity within the hippocampus, adjusted for demographics, hippocampal volume, and white matter. This was repeated in participants without evident hippocampal volume loss, because in these participants the visible damage might not yet have already started, whereas damage might have started on a microstructural level., Results: 43 participants developed dementia (8.6%), resulting in a 5.5-year cumulative risk of 11.1% (95%CI 7.7-14.6). Higher mean diffusivity was associated with an increased 5-year risk of dementia. In the subgroup of participants with the upper half hippocampal volume, higher hippocampal mean diffusivity, more than doubled the 5-year risk of dementia., Conclusion: This is the first prospective study showing a relation between a higher baseline hippocampal mean diffusivity and the risk of incident dementia in elderly with small vessel disease at 5-year follow-up, independent of hippocampal volume and white matter volume., (© 2015 Wiley Periodicals, Inc.)

Background and Purpose: Risk factors for IS in young adults differ between genders and evolve with age, but data on the age- and gender-specific differences by stroke etiology are scare. These features were compared based on individual patient data from 15 European stroke centers., Methods: Stroke etiology was reported in detail for 3331 patients aged 15-49 years with first-ever IS according to Trial of Org in Acute Stroke Treatment (TOAST) criteria: large-artery atherosclerosis (LAA), cardioembolism (CE), small-vessel occlusion (SVO), other determined etiology, or undetermined etiology. CE was categorized into low- and high-risk sources. Other determined group was divided into dissection and other non-dissection causes. Comparisons were done using logistic regression, adjusting for age, gender, and center heterogeneity., Results: Etiology remained undetermined in 39.6%. Other determined etiology was found in 21.6%, CE in 17.3%, SVO in 12.2%, and LAA in 9.3%. Other determined etiology was more common in females and younger patients, with cervical artery dissection being the single most common etiology (12.8%). CE was more common in younger patients. Within CE, the most frequent high-risk sources were atrial fibrillation/flutter (15.1%) and cardiomyopathy (11.5%). LAA, high-risk sources of CE, and SVO were more common in males. LAA and SVO showed an increasing frequency with age. No significant etiologic distribution differences were found amongst southern, central, or northern Europe., Conclusions: The etiology of IS in young adults has clear gender-specific patterns that change with age. A notable portion of these patients remains without an evident stroke mechanism according to TOAST criteria., (© 2013 The Author(s) European Journal of Neurology © 2013 EFNS.)

Background: Little is known about the incidence and risk of seizures after stroke in young adults. Especially in the young seizures might dramatically influence prognosis and quality of life. We therefore investigated the long-term incidence and risk of post-stroke epilepsy in young adults with a transient ischemic attack (TIA), ischemic stroke (IS) or intracerebral hemorrhage (ICH)., Methods and Findings: We performed a prospective cohort study among 697 consecutive patients with a first-ever TIA, IS or ICH, aged 18-50 years, admitted to our hospital between 1-1-1980 till 1-11-2010. The occurrence of epilepsy was assessed by standardized questionnaires and verified by a neurologist. Cumulative risks were estimated with Kaplan-Meier analysis. Cox proportional hazard models were used to calculate relative risks. After mean follow-up of 9.1 years (SD 8.2), 79 (11.3%) patients developed post-stroke epilepsy and 39 patients (5.6%) developed epilepsy with recurrent seizures. Patients with an initial late seizure more often developed recurrent seizures than patients with an initial early seizure. Cumulative risk of epilepsy was 31%, 16% and 5% for patients with an ICH, IS and TIA respectively (Logrank test ICH and IS versus TIA p<0.001). Cumulative risk of epilepsy with recurrent seizures was 23%, 8% and 4% respectively (Logrank ICH versus IS p = 0.05, ICH versus TIA p<0.001, IS versus TIA p = 0.01). In addition a high NIHSS was a significant predictor of both epilepsy and epilepsy with recurrent seizures (HR 1.07, 95% CI 1.03-1.11 and 1.08, 95% CI 1.02-1.14)., Conclusions: Post-stroke epilepsy is much more common than previously thought. Especially patients with an ICH and a high NIHSS are at high risk. This calls upon the question whether a subgroup could be identified which benefits from the use of prophylactic antiepileptic medication. Future studies should be executed to investigate risk factors and the effect of post-stroke epilepsy on quality of life.

Background and Purpose: We compared among young patients with ischemic stroke the distribution of vascular risk factors among sex, age groups, and 3 distinct geographic regions in Europe., Methods: We included patients with first-ever ischemic stroke aged 15 to 49 years from existing hospital- or population-based prospective or consecutive young stroke registries involving 15 cities in 12 countries. Geographic regions were defined as northern (Finland, Norway), central (Austria, Belgium, France, Germany, Hungary, The Netherlands, Switzerland), and southern (Greece, Italy, Turkey) Europe. Hierarchical regression models were used for comparisons., Results: In the study cohort (n=3944), the 3 most frequent risk factors were current smoking (48.7%), dyslipidemia (45.8%), and hypertension (35.9%). Compared with central (n=1868; median age, 43 years) and northern (n=1330; median age, 44 years) European patients, southern Europeans (n=746; median age, 41 years) were younger. No sex difference emerged between the regions, male:female ratio being 0.7 in those aged <34 years and reaching 1.7 in those aged 45 to 49 years. After accounting for confounders, no risk-factor differences emerged at the region level. Compared with females, males were older and they more frequently had dyslipidemia or coronary heart disease, or were smokers, irrespective of region. In both sexes, prevalence of family history of stroke, dyslipidemia, smoking, hypertension, diabetes mellitus, coronary heart disease, peripheral arterial disease, and atrial fibrillation positively correlated with age across all regions., Conclusions: Primary preventive strategies for ischemic stroke in young adults-having high rate of modifiable risk factors-should be targeted according to sex and age at continental level.