BackgroundAlthough childhood adversity is a potent determinant of psychopathology, relatively little is known about how the characteristics of adversity exposure, including its developmental timing or duration, influence subsequent mental health outcomes. This study compared three models from life course theory (recency, accumulation, sensitive period) to determine which one(s) best explained this relationship.MethodsProspective data came from the Avon Longitudinal Study of Parents and Children (n= 7476). Four adversities commonly linked to psychopathology (caregiver physical/emotional abuse; sexual/physical abuse; financial stress; parent legal problems) were measured repeatedly from birth to age 8. Using a statistical modeling approach grounded in least angle regression, we determined the theoretical model(s) explaining the most variability (r2) in psychopathology symptoms measured at age 8 using the Strengths and Difficulties Questionnaire and evaluated the magnitude of each association.ResultsRecencywas the best fitting theoretical model for the effect of physical/sexual abuse (girlsr2= 2.35%; boysr2= 1.68%). Bothrecency(girlsr2= 1.55%) andaccumulation(boysr2= 1.71%) were the best fitting models for caregiver physical/emotional abuse.Sensitive periodmodels were chosen alone (parent legal problems in boysr2= 0.29%) and withaccumulation(financial stress in girlsr2= 3.08%) more rarely. Substantial effect sizes were observed (standardized mean differences = 0.22–1.18).ConclusionsChild psychopathology symptoms are primarily explained by recency and accumulation models. Evidence for sensitive periods did not emerge strongly in these data. These findings underscore the need to measure the characteristics of adversity, which can aid in understanding disease mechanisms and determining how best to reduce the consequences of exposure to adversity.

Emotion recognition skills are essential for social communication. Deficits in these skills have been implicated in mental disorders. Prior studies of clinical and high-risk samples have consistently shown that children exposed to adversity are more likely than their unexposed peers to have emotion recognition skills deficits. However, only one population-based study has examined this association. We analyzed data from children participating in the Avon Longitudinal Study of Parents and Children, a prospective birth cohort ( n  = 6,506). We examined the association between eight adversities, assessed repeatedly from birth to age 8 (caregiver physical or emotional abuse; sexual or physical abuse; maternal psychopathology; one adult in the household; family instability; financial stress; parent legal problems; neighborhood disadvantage) and the ability to recognize facial displays of emotion measured using the faces subtest of the Diagnostic Assessment of Non-Verbal Accuracy (DANVA) at age 8.5 years. In addition to examining the role of exposure (vs. nonexposure) to each type of adversity, we also evaluated the role of the timing, duration, and recency of each adversity using a Least Angle Regression variable selection procedure. Over three-quarters of the sample experienced at least one adversity. We found no evidence to support an association between emotion recognition deficits and previous exposure to adversity, either in terms of total lifetime exposure, timing, duration, or recency, or when stratifying by sex. Results from the largest population-based sample suggest that even extreme forms of adversity are unrelated to emotion recognition deficits as measured by the DANVA, suggesting the possible immutability of emotion recognition in the general population. These findings emphasize the importance of population-based studies to generate generalizable results.

Background: Emotion recognition skills are essential for social communication. Deficits in these skills have been implicated in mental disorders. Prior studies of clinical and high-risk samples have consistently shown that children exposed to adversity are more likely than their unexposed peers to have emotion recognition skills deficits. However, only one population-based study has examined this association. Methods: We analyzed data from children participating in the Avon Longitudinal Study of Parents and Children, a prospective birth cohort (n=6,506). We examined the association between eight adversities, assessed repeatedly from birth to age 8 (caregiver physical or emotional abuse; sexual or physical abuse; maternal psychopathology; one adult in the household; family instability; financial stress; parent legal problems; neighborhood disadvantage) and the ability to recognize facial displays of emotion measured using the faces subtest of the Diagnostic Assessment of Non-Verbal Accuracy (DANVA) at age 8.5 years. In addition to examining the role of exposure (vs. non-exposure) to each type of adversity, we also evaluated the role of the timing, duration, and recency of each adversity using a Least Angle Regression variable selection procedure. Results: Over three-quarters of the sample experienced at least one adversity. We found no evidence to support an association between emotion recognition deficits and previous exposure to adversity, either in terms of total lifetime exposure, timing, duration, or recency, or when stratifying by sex. Conclusions: Results from the largest population-based sample suggest that even extreme forms of adversity are unrelated to emotion recognition deficits as measured by the DANVA, suggesting the possible immutability of emotion recognition in the general population. These findings emphasize the importance of population-based studies to generate generalizable results.

BACKGROUND Emotion recognition skills are essential for social communication. Deficits in these skills have been implicated in mental disorders. Prior studies of clinical and high-risk samples have consistently shown that children exposed to adversity are more likely than their unexposed peers to have emotion recognition skills deficits. However, only one population-based study has examined this association. METHODS We analyzed data from children participating in the Avon Longitudinal Study of Parents and Children, a prospective birth cohort (n = 6,506). We examined the association between eight adversities, assessed repeatedly from birth to age 8 (caregiver physical or emotional abuse; sexual or physical abuse; maternal psychopathology; one adult in the household; family instability; financial stress; parent legal problems; neighborhood disadvantage) and the ability to recognize facial displays of emotion measured using the faces subtest of the Diagnostic Assessment of Non-Verbal Accuracy (DANVA) at age 8.5 years. In addition to examining the role of exposure (vs. nonexposure) to each type of adversity, we also evaluated the role of the timing, duration, and recency of each adversity using a Least Angle Regression variable selection procedure. RESULTS Over three-quarters of the sample experienced at least one adversity. We found no evidence to support an association between emotion recognition deficits and previous exposure to adversity, either in terms of total lifetime exposure, timing, duration, or recency, or when stratifying by sex. CONCLUSIONS Results from the largest population-based sample suggest that even extreme forms of adversity are unrelated to emotion recognition deficits as measured by the DANVA, suggesting the possible immutability of emotion recognition in the general population. These findings emphasize the importance of population-based studies to generate generalizable results.

Objective: To determine whether common variants in familial cerebral small vessel disease (SVD) genes confer risk of sporadic cerebral SVD. Methods: We meta-analyzed genotype data from individuals of European ancestry to determine associations of common single nucleotide polymorphisms (SNPs) in 6 familial cerebral SVD genes (COL4A1, COL4A2, NOTCH3, HTRA1, TREX1, and CECR1) with intracerebral hemorrhage (ICH) (deep, lobar, all; 1,878 cases, 2,830 controls) and ischemic stroke (IS) (lacunar, cardioembolic, large vessel disease, all; 19,569 cases, 37,853 controls). We applied data quality filters and set statistical significance thresholds accounting for linkage disequilibrium and multiple testing. Results: A locus in COL4A2 was associated (significance threshold p < 3.5 × 10−4) with both lacunar IS (lead SNP rs9515201: odds ratio [OR] 1.17, 95% confidence interval [CI] 1.11–1.24, p = 6.62 × 10−8) and deep ICH (lead SNP rs4771674: OR 1.28, 95% CI 1.13–1.44, p = 5.76 × 10−5). A SNP in HTRA1 was associated (significance threshold p < 5.5 × 10−4) with lacunar IS (rs79043147: OR 1.23, 95% CI 1.10–1.37, p = 1.90 × 10−4) and less robustly with deep ICH. There was no clear evidence for association of common variants in either COL4A2 or HTRA1 with non-SVD strokes or in any of the other genes with any stroke phenotype. Conclusions: These results provide evidence of shared genetic determinants and suggest common pathophysiologic mechanisms of distinct ischemic and hemorrhagic cerebral SVD stroke phenotypes, offering new insights into the causal mechanisms of cerebral SVD.

Primary intracerebral haemorrhage and lacunar ischaemic stroke are acute manifestations of progressive cerebral microvascular disease. Current paradigms suggest atherosclerosis is a chronic, dynamic, inflammatory condition precipitated in response to endothelial injury from various environmental challenges. Myeloperoxidase plays a central role in initiation and progression of vascular inflammation, but prior studies linking myeloperoxidase with stroke risk have been inconclusive. We hypothesized that genetic determinants of myeloperoxidase levels influence the development of vascular instability, leading to increased primary intracerebral haemorrhage and lacunar stroke risk. We used a discovery cohort of 1409 primary intracerebral haemorrhage cases and 1624 controls from three studies, an extension cohort of 12 577 ischaemic stroke cases and 25 643 controls from NINDS-SiGN, and a validation cohort of 10 307 ischaemic stroke cases and 29 326 controls from METASTROKE Consortium with genome-wide genotyping to test this hypothesis. A genetic risk score reflecting elevated myeloperoxidase levels was constructed from 15 common single nucleotide polymorphisms identified from prior genome-wide studies of circulating myeloperoxidase levels (P < 5 × 10-6). This genetic risk score was used as the independent variable in multivariable regression models for association with primary intracerebral haemorrhage and ischaemic stroke subtypes. We used fixed effects meta-analyses to pool estimates across studies. We also used Cox regression models in a prospective cohort of 174 primary intracerebral haemorrhage survivors for association with intracerebral haemorrhage recurrence. We present effects of myeloperoxidase elevating single nucleotide polymorphisms on stroke risk per risk allele, corresponding to a one allele increase in the myeloperoxidase increasing genetic risk score. Genetic determinants of elevated circulating myeloperoxidase levels were associated with both primary intracerebral haemorrhage risk (odds ratio, 1.07, P = 0.04) and recurrent intracerebral haemorrhage risk (hazards ratio, 1.45, P = 0.006). In analysis of ischaemic stroke subtypes, the myeloperoxidase increasing genetic risk score was strongly associated with lacunar subtype only (odds ratio, 1.05, P = 0.0012). These results, demonstrating that common genetic variants that increase myeloperoxidase levels increase risk of primary intracerebral haemorrhage and lacunar stroke, directly implicate the myeloperoxidase pathway in the pathogenesis of cerebral small vessel disease. Because genetic variants are not influenced by environmental exposures, these results provide new support for a causal rather than bystander role for myeloperoxidase in the progression of cerebrovascular disease. Furthermore, these results support a rationale for chronic inflammation as a potential modifiable stroke risk mechanism, and suggest that immune-targeted therapies could be useful for treatment and prevention of cerebrovascular disease.

Exposure to “early life adversity” (e.g., in the first two decades of life) is known to predict DNA methylation (DNAm). However, few studies have investigated whether adversity has time-dependent effects, varying based on the age at exposure.

The CHARGE consortium is an investigator-initiated collaboration to facilitate meta-analyses of genome-wide association studies (GWAS) and genomic analyses based on next generation sequencing (NGS), among multiple large and well-phenotyped population-based cohort studies around the world (http://www.chargeconsortium.com). Within the neuro-CHARGE working group, we are presenting an update of ongoing genomic studies on MRI-markers of cerebrovascular disease. Large population-based studies have shown that the burden of cerebrovascular disease extends far beyond that of clinical stroke. MRI-markers of cerebral small vessel disease, such as white matter hyperintensities (WMH), small subcortical brain infarcts, microbleeds, or dilated perivascular spaces, are particularly frequent in older community persons. These markers portend an increased risk of stroke, dementia, and premature death, and were shown to have a high heritability, especially WMH burden. Interestingly recent work has revealed genetic risk variants between WMH burden and stroke. To account for the major role of high blood pressure in the occurrence of WMH, we are performing a GWAS of WMH burden stratified on hypertension status, as well as a joint meta-analysis to account for gene-environment interaction with hypertension. Moreover, based on prior epidemiologic and histologic data suggesting that the pathogenesis of WMH may differ according to their location, we are running separate GWAS for periventricular and deep WMH burden. A GWAS of cerebral microbleeds is being finalized. We are also exploring the role of vascular risk factors in the occurrence of dementia by examining the relation of genetic risk scores for these factors with MRI-markers of brain aging and cerebrovascular disease. Finally, several NGS projects are being conducted to identify rare variants associated with WMH burden and lacunar brain infarcts. Additional projects are also currently being designed, including GWAS of novel MRI phenotypes, such as composite measures of cerebral small vessel disease, as well as lifetime, and epigenomic approaches. 2016.002 Modeling acute lesion volume and topography for genetic analysis (MRI-GENIE study) Ona Wu, PhD; Stefan Winzeck, MS; Steven J.T. Mocking, MS; Markus D. Schirmer, PhD; Mark J.R.J. Bouts, PhD; Elissa C. McIntosh, MA; Anne-Katrin Giese, MD; Joseph P. Broderick, MD; Jordi Jimenez-Conde, MD, PhD; Christina Jern, MD, PhD; Brett M. Kissela, MD, MS, Steven J. Kittner, MD, MPH; Dawn O. Kleindorfer, MD; Robin Lemmens, MD, PhD; Arne Lindgren, MD, PhD; James F. Meschia, MD; Braxton D. Mitchell, PhD, MPH; Jonathan Rosand, MD, MSc; Tatjana Rundek, MD, PhD; Ralph L. Sacco, MD, MS; Reinhold Schmidt, MD; Pankaj Sharma, MD, PhD; Agnieszka Slowik, MD, PhD, Vincent N.S. Thijs, MD, PhD; Daniel Woo, MD, MS, Bradford B. Worrall, MD, MSc; Natalia S. Rost, MD, MPH Athinoula A Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown; University Division of Anaesthesia, Department of Medicine, Cambridge University, UK; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA; Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, OH; Department of Neurology, Neurovascular Research Group (NEUVAS), IMIM-Hospital del Mar (Institut Hospital del Mar d’Investigacions Mèdiques), Universitat Autonoma de Barcelona, Spain; Institute of Biomedicine, the Sahlgrenska Academy at University of Gothenburg, Sweden; Department of Neurology, University of Maryland School of Medicine and Veterans Affairs Maryland Health Care System, Baltimore; KU Leuven—University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND), Leuven, Belgium; VIB, Vesalius Research Center, Laboratory of Neurobiology, University Hospitals Leuven, Department of Neurology, Belgium; Department of Clinical Sciences Lund, Neurology, Lund University; Department of Neurology and Rehabilitation Medicine, Neurology, Skåne University Hospital, Lund, Sweden; Department of Neurology, Mayo Clinic, Jacksonville, FL; Department of Medicine, University of Maryland School of Medicine, Baltimore; Geriatric Research and Education Clinical Center, Veterans Administration Medical Center, Baltimore, MD; Department of Neurology, Miller School of Medicine, University of Miami, FL; Department of Neurology, Clinical Division of Neurogeriatrics, Medical University Graz, Austria; Institute of Cardiovascular Research, Royal Holloway University of London (ICR2UL), Egham, Ashford and St Peter’s Hospitals, UK; Department of Neurology, Jagiellonian University Medical College, Krakow, Poland; Department of Neurology Austin Health, Melbourne Brain Center, Florey Institute of Neuroscience and Mental Health, Heidelberg, Australia; and Departments of Neurology and Public Health Sciences, University of Virginia, Charlottesville, VA. OBJECTIVE: To investigate the relationship between acute ischemic lesion location and volumes and genetics with admission stroke severity and long-term outcome, an automated lesion segmentation algorithm was developed. BACKGROUND: One of the primary goals of the MRI-Genetics Interface Exploration study (MRI-GENIE) is to develop clinical MRI scan analysis tools that will advance genetic discovery in stroke. To incorporate lesion volumes and topology into stroke genetic analysis studies, thousands of datasets from multiple centers will need to be analyzed. We therefore developed an automated lesion segmentation algorithm. DESIGN/METHODS: Lesion segmentation was performed by randomized classification forests (RF) on a voxel-wise basis. 9 3 9 3 1 patches of the input, consisting of the apparent diffusion coefficient map, isotropic diffusionweighted image, and non-diffusion-weighted image, resulted in 243 features. Optimal patch size was determined in a 5-fold cross-validation with 50 patients. The final segmentation model was trained on 67 patients and applied to 1,197 independent datasets from the Stroke Genetics Network (SiGN) Repository. The RF outputs were thresholded then further processed using post-hoc regional analyses. All images were spatially normalized to the MNI 1 mm atlas using non-linear co-registration (MNI Autoreg). RESULTS: Median (IQR) acute DWI volumes were 4.3 (0–22.0) cm. The figure shows the incidence map of lesions for all 1,197 subjects (maximum incidence was 138). The frequency of stroke lesions was comparable for both left and right hemispheres and consistent with previously published studies involving single centers. CONCLUSIONS: Automatic acute DWI lesion segmentation is feasible. Studies investigating the association between lesion topography and lesion volumes with genetics, admission stroke severity scores and long term functional outcomes in large multi-center datasets are therefore realistic. Study Supported By: NIH-Neurological Disorders and Stroke (MRI-GENIE study: R01NS086905—PI N.S. Rost; K23NS064052, R01NS082285—N.S. Rost; SiGN: U01 NS069208—J. Rosand, S.J. Kittner; R01NS063925, R01NS086905, R01NS059775, R01NS082285, P50NS051343, U01NS069208—O. Wu). Disclosure: The authors declare no conflict of interest. 2016.003 Genome-wide association studies of disease severity in neurocritical care: Interim analysis of spontaneous intracerebral hemorrhage volume Guido J. Falcone; Daniel Woo; Miriam R. Raffeld; Alessandro Biffi; Chia-Ling Phuah; Joshua N. Goldstein; David L. Tirschwell; Magdy Selim; Scott L. Silliman; Bradford B. Worrall; James F. Meschia; Jordi Jimenez-Conde; Arne Lindgren; Christopher D. Anderson; Jonathan Rosand Center for Human Genetic Research, Massachusetts General Hospital, Boston; Department of Neurology, University of Cincinnati College of Medicine, OH; Department of Emergency Medicine, Massachusetts General Hospital, Boston; Stroke Center, Harborview Medical Center, University of Washington, Seattle; Department of Neurology, Stroke Division, Beth Israel Deaconess Medical Center, Boston, MA; Department of Neurology, University of Florida College of Medicine, Jacksonville; 2016.002: Modeling acute lesion volume and topography for genetic analysis (MRI-GENIE study) 2016.003: Genome-wide association studies of disease severity in neurocritical care: Interim analysis of spontaneous intracerebral hemorrhage volume S2 Neurology: Genetics ISGC 2016 Abstracts a 2017 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Department of Neurology and Public Health Sciences, University of Virginia Health System, Charlottesville, Department of Neurology, Mayo Clinic, Jacksonville, FL; Neurovascular Research Unit, Department of Neurology, IMIM (Institut Hospital del Mar d’Investigacions Mèdiques), Universitat Autonoma de Barcelona, Spain; Department of Neurology, Skåne University Hospital, Lund, Sweden. OBJECTIVE: We report an interim analysis of the first GWAS of ICH volume undertaken by the International Stroke Genetics Consortium. BACKGROUND: Spontaneous intracerebral hemorrhage (ICH) carries a grim prognosis and has limited treatment options. ICH volume remains the most potent predictor of outcome. Genome-wide association studies (GWAS) constitute a powerful technique for identifying novel biological pathways and drug targets for human disease. DESIGN/METHODS: Two-stage (discovery and replication) cohort study that included subjects from a multicenter US study (discovery) and 2 European studies (replication). We utilized admission head CT to calculate hematoma volume and classify ICH cases as lobar or non-lobar. After genotyping (Illumina 610 platform) and imputation, 7 million genetic variants were available for testing. Association testing was carried out using linear regression. Signals with p , 5 3 10 were pursued in repli

Objective: The study aims to evaluate the association between exposure to childhood adversity and insomnia, with an emphasis on the role of adversity type, timing, and accumulation (i.e., the number of specific types of adversities the child reported being exposed to).Methods: Our analytic sample comprised 9582 adolescents from the National Comorbidity Survey Replication Adolescent Supplement (NCS-A), a nationally representative population-based sample. We examined the association between 18 different types of retrospectively reported adversities (capturing interpersonal violence, accidents and injuries, social network or witnessing events, and other adverse events) and risk of self-reported past-year insomnia. We also examined whether the age at first exposure to adversity was associated with the risk of insomnia, and whether exposure to a greater number of different types of adversities (ie, accumulation) conferred an elevated risk of insomnia. In addition, we performed a sensitivity analysis excluding adolescents with a past-year diagnosis of major depression, dysthymia, post-traumatic stress disorder (PTSD), or generalized anxiety disorder.Results: Almost one-third of adolescents reported insomnia, with a higher prevalence among girls and those from racial/ethnic minority groups. Adolescents exposed to at least one childhood adversity of any type (59.41%) were more likely than their nonexposed peers to experience insomnia (across adversities, prevalence ratios (PRs) ranged from 1.31 to 1.89). Risk of insomnia differed based on the age at first exposure to adversity as well as the type of adversity. Adolescents exposed to a greater number of different types of adversities had a higher risk of insomnia compared to those experiencing fewer adversities. These results were similar, by and large, to those obtained after excluding adolescents with at least one of the four past-year psychiatric disorders.Conclusions: Exposure to adversity confers an elevated risk of insomnia. This association varied by type, timing, and accumulation of exposure and did not appear to be driven by psychiatric disorders. Given the well-documented physical and mental health consequences of insomnia, such findings further support the need for practitioners to screen children for exposure to childhood adversity and insomnia symptoms. (C) 2016 Elsevier B.V. All rights reserved.

OBJECTIVE:We aimed to describe the temporal variation in circulating lipid levels among patients with intracerebral hemorrhage (ICH) and investigate their association with ICH risk. METHODS:This was a single-center, retrospective, longitudinal, case-control analysis using cases drawn from an ongoing cohort study of primary ICH and controls drawn from a hospital-based clinical data registry. Piecewise linear mixed-effect random coefficient models were used to determine the significance of changes in serum lipid trends on ICH risk. RESULTS:Two hundred twelve ICH cases and 301 control individuals were analyzed. Overall trends in serum total cholesterol (TC) and low-density lipoprotein (LDL) levels differed between ICH cases and non-ICH controls (p = 0.00001 and p = 0.0092, respectively). Patients with ICH experience accelerated decline in serum TC and LDL levels during 6 months immediately preceding ICH, compared with levels between 6 and 24 months pre-ICH (TC: -29.25 mg/dL, p = 0.001; LDL: -21.48 mg/dL, p = 0.0038), which was not observed in non-ICH controls. Subgroup analysis confirmed that this phenomenon cannot be attributed to statin or alcohol exposure. Serum triglycerides and high-density lipoprotein trends did not differ between groups. CONCLUSIONS:Longitudinal lipid levels differ between ICH cases and non-ICH controls, most notably for a decline in serum TC and LDL levels within 6 months preceding primary ICH, independent of statin or alcohol use. These changes in serum TC and LDL trends suggest a biological pathway that precipitates ICH occurrence. Further studies are needed to replicate these results and characterize rate of change in serum lipids as a potential biomarker of impending acute cerebral injury.

HomeStrokeVol. 47, No. 4International Stroke Genetics Consortium Update Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBInternational Stroke Genetics Consortium Update Miriam R. Raffeld, BA, Stephanie Debette, MD, PhD and Daniel Woo, MD, MS Miriam R. RaffeldMiriam R. Raffeld From the Department of Neurology, Center for Human Genetic Research, Massachusetts General Hospital, Boston (M.R.R.); Department of Neurology, Lariboisière Hospital, Paris 7 University, DHU Neurovasc Sorbonne Paris Cité, Paris, France (S.D.); Inserm U897, Bordeaux University, Talence, France (S.D.); and Department of Neurology, University of Cincinnati Medical Center, OH (D.W.). , Stephanie DebetteStephanie Debette From the Department of Neurology, Center for Human Genetic Research, Massachusetts General Hospital, Boston (M.R.R.); Department of Neurology, Lariboisière Hospital, Paris 7 University, DHU Neurovasc Sorbonne Paris Cité, Paris, France (S.D.); Inserm U897, Bordeaux University, Talence, France (S.D.); and Department of Neurology, University of Cincinnati Medical Center, OH (D.W.). and Daniel WooDaniel Woo From the Department of Neurology, Center for Human Genetic Research, Massachusetts General Hospital, Boston (M.R.R.); Department of Neurology, Lariboisière Hospital, Paris 7 University, DHU Neurovasc Sorbonne Paris Cité, Paris, France (S.D.); Inserm U897, Bordeaux University, Talence, France (S.D.); and Department of Neurology, University of Cincinnati Medical Center, OH (D.W.). Originally published23 Feb 2016https://doi.org/10.1161/STROKEAHA.116.012682Stroke. 2016;47:1144–1145Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2016: Previous Version 1 Created in April 2007, the International Stroke Genetics Consortium (ISGC) has grown into scientific community's global organizing force for stroke genetics, open to all who can contribute to its mission. Stroke is a leading cause of death worldwide,1 with 15 million people suffering a stroke per year.1 Intracerebral hemorrhage, which makes up 15% of all stroke in the United States,2 results in a 50% rate of severe disability or death.3,4 Although the major cerebrovascular risk factors of hypertension, cardiac disease, diabetes mellitus, and the influence of hyperlipidemia have been well established, a substantial portion of stroke is not explained by these risk factors alone and biological susceptibility to known risk factors remains to be discovered. The ISGC has been at the forefront of genetic discovery to understand the mechanisms behind stroke. Formed with the principal value that collaboration and coordinated effort will produce the highest quality results in the most efficient manner (Table), the ISGC has developed other major stroke collaborations, including the METASTROKE consortium and the SiGN Consortium, and partnered with the CHARGE consortium. The ISGC has identified 8 loci associated with ischemic stroke, 6 loci associated with intracerebral hemorrhage, 5 loci associated with intracranial aneurysm, and 1 locus associated with cervical artery dissection in collaboration with the CADISP consortium. Each of these findings was genome-wide significant with replication in an independent sample.Table. ISGC Founding PrinciplesCerebrovascular disease is a complex disorder influenced by variation in many genetic and nongenetic exposures, each of which contributes only a small influence to disease risk. Therefore, large (larger than any single center can assemble on its own) well-characterized sample sets will be necessary to discover these exposures.ISGC principles of collaboration. The ISGC is open to all who can contribute. All contributions are fairly recognized in publications. We work together in a spirit of cooperation and open communication to promote the best science in the present and the best science in the future.ISGC indicates International Stroke Genetics Consortium.Collaboration is the cornerstone of the ISGC because we continue to increase the number of samples available for research to uncover the genetics underlying stroke. The ISGC has grown substantially during the years, and now encompasses >250 members from 6 continents, spanning >50 countries. With the enormous growth of the ISGC, we are excited to announce the ISGC's Platform for Accelerating Genetic Discovery in Cerebrovascular Disease, which was awarded funding earlier this year. This platform will enable investigators around the world to access ISGC data, both summary and individual level data, and have access to, as well as contribute, samples all in a manner consistent with the informed consent provided by participating research subjects.Through collaboration, the ISGC has published a total of 52 articles, including guidelines for collecting biological samples and standardizing phenotype data to create harmonious data sets, and identification of ischemic and hemorrhagic stroke susceptibility loci. See www.strokegenetics.org for current workshops, all publications, and news from the ISGC.Education is another important aspect of the ISGC. The ISGC holds biannual workshops with our most recent workshop in Barcelona, Spain and we are looking forward to our 19th workshop on April, 2016 in Cambridge, MA. The 20th workshop will be held in Milan, Italy on November 3 and 4, 2016. The workshops allow for collaborators to come together and discuss cutting-edge topics in stroke genetics and ongoing ISGC projects. In addition, every year the ISGC awards a travel scholarship to allow 1 junior researcher to attend the workshop. This year we were pleased to award the scholarship to Stacie Demel, DO, PhD from the University of Cincinnati.We are excited for another productive year that includes the launch of the Platform for Accelerating Genetic Discovery in Cerebrovascular Disease and the upcoming workshop on April 28th and 29th at the Broad Institute of MIT and Harvard, hosted jointly with Massachusetts General Hospital and Harvard Medical School. The ISGC welcomes all with the skills and commitment to contribute to our efforts. Those interested in becoming a member or who seek more information about the consortium should contact Daniel Woo, MD ([email protected]), Chair of the Steering Committee.Sources of FundingThis work was funded by Wellcome Trust awards, The National Institute of Neurological Diseases and Stroke awards, and The National Institutes of Health.DisclosuresNone.FootnotesCorrespondence to Daniel Woo, MD, MS, Department of Neurology, University of Cincinnati Medical Center, 222 Piedmont Ave, No. 3200, Cincinnati, OH 45219. Email [email protected]References1. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et alAmerican Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics–2015 update: a report from the American Heart Association.Circulation. 2015; 131:e29–e322. doi: 10.1161/CIR.0000000000000152.LinkGoogle Scholar2. Qureshi AI, Tuhrim S, Broderick JP, Batjer HH, Hondo H, Hanley DF.Spontaneous intracerebral hemorrhage.N Engl J Med. 2001; 344:1450–1460. doi: 10.1056/NEJM200105103441907.CrossrefMedlineGoogle Scholar3. Broderick J, Connolly S, Feldmann E, Hanley D, Kase C, Krieger D, et alAmerican Heart Association/American Stroke Association Stroke Council; American Heart Association/American Stroke Association High Blood Pressure Research Council; Quality of Care and Outcomes in Research Interdisciplinary Working Group. Guidelines for the management of spontaneous intracerebral hemorrhage in adults: 2007 update: a guideline from the American Heart Association/American Stroke Association Stroke Council, High Blood Pressure Research Council, and the Quality of Care and Outcomes in Research Interdisciplinary Working Group.Circulation. 2007; 116:e391–e413. doi: 10.1161/CIRCULATIONAHA.107.183689.LinkGoogle Scholar4. Rosand J, Eckman MH, Knudsen KA, Singer DE, Greenberg SM.The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage.Arch Intern Med. 2004; 164:880–884. doi: 10.1001/archinte.164.8.880.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Vadgama N, Lamont D, Hardy J, Nasir J and Lovering R (2019) Distinct proteomic profiles in monozygotic twins discordant for ischaemic stroke, Molecular and Cellular Biochemistry, 10.1007/s11010-019-03501-2, 456:1-2, (157-165), Online publication date: 1-Jun-2019. Kabir A, Ruiz C, Alvarez S and Moonis M (2018) Regression, Classification and Ensemble Machine Learning Approaches to Forecasting Clinical Outcomes in Ischemic Stroke Biomedical Engineering Systems and Technologies, 10.1007/978-3-319-94806-5_20, (376-402), . Zheng F, Zhou Y, Zeng Y, Liu T, Yang Z, Tang T, Luo J and Wang Y (2020) Proteomics Analysis of Brain Tissue in a Rat Model of Ischemic Stroke in the Acute Phase, Frontiers in Molecular Neuroscience, 10.3389/fnmol.2020.00027, 13 April 2016Vol 47, Issue 4 Advertisement Article InformationMetrics © 2016 American Heart Association, Inc.https://doi.org/10.1161/STROKEAHA.116.012682PMID: 26906919 Manuscript receivedJanuary 6, 2016Manuscript acceptedJanuary 14, 2016Originally publishedFebruary 23, 2016 KeywordsgeneticsepidemiologystrokePDF download Advertisement SubjectsCerebrovascular Disease/StrokeGeneticsIntracranial HemorrhageIschemic Stroke

Introduction: Primary intracerebral hemorrhage (ICH) remains one of the most severe forms of acute cerebrovascular disease. APOE ε2 and ε4 are risk factors for primary ICH, and also involved in regulation of circulating lipid levels. Hypercholesterolemia has been associated with reduced ICH risk. However, the biological mechanisms mediating the roles of APOE and serum lipids on ICH risk remain unclear. Given the pleiotropic relationship between APOE, ICH, and serum lipid levels, we sought to determine the influence of APOE genotype on temporal serum lipid trends before and after ICH. Methods: We performed a single-center retrospective longitudinal cohort analysis using subjects with known APOE genotype drawn from an ongoing cohort study of primary ICH. Serum lipid measurements for total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) collected within 2 years preceding and following index ICH were extracted from electronic medical records (EMR). Piecewise linear mixed-effects random-coefficent models were used to compare APOE allele-specific effects on changes in serum lipid trends in ICH. Results: 124 ICH cases were analyzed. APOE ε4 carriers had significantly greater rates of decline in serum TC and LDL levels within 6 months prior to ICH (TC: -7.30 mg/dL/month, p=0.0035; LDL: -8.44 mg/dL/month, p=0.0001) compared to non-carriers (TC: -3.79 mg/dL/month, p=0.17; LDL: -2.39 mg/dL/month, p=0.55). In contrast, TC and LDL trends for APOE ε2 carriers were not significantly altered within the same time period. APOE genotype had no associations with serum HDL or TG trends. Conclusions: APOE allele status is a strong predictor of subacute serum TC and LDL changes preceding ICH. Our results have implications for ongoing efforts in dissecting the role of dyslipidemia in cerebrovascular disease risk. While further studies are needed, our observation that APOE ε4 influences serum lipid trends preceding ICH provides additional insight towards lipid-dependent and lipid-independent APOE-genotype specific effects on stroke risk and suggests that characterization of the metabolic role of APOE is needed to improve understanding of APOE biology in cerebrovascular disease.

In patients with intracerebral hemorrhage (ICH), it is not clear if hypernatremia is merely a marker of disease severity or if elevated sodium levels are harmful. We hypothesized that hypernatremia at hospital discharge in primary ICH patients would be associated with increased mortality following discharge.

Introduction: Dyslipidemia plays a paradoxical role in some forms of cerebrovascular disease. Unlike its relationship with ischemic stroke, hypercholesterolemia has been associated with reduced risk of intracerebral hemorrhage (ICH). However, serum lipid levels have wide variation coefficients, and point estimates are likely not representative of long-term exposures. Understanding the temporal trends in serum lipid levels and their association with ICH may improve understanding of the biology of dyslipidemia in ICH. We sought to determine the course of temporal variations in total cholesterol (TC), low-density lipoprotein (LDL), triglycerides (TG) and high-density lipoprotein (HDL) over 48 months before and after primary ICH. Methods: We performed a single-center retrospective longitudinal case-control analysis using cases drawn from an ongoing cohort study of primary ICH and controls drawn from a clinical data registry of patients hospitalized for acute non-cerebral events. Piecewise linear mixed-effects models were used to compare the impact of ICH or hospitalization on lipid trends. Results: 212 ICH cases and 301 control subjects were analyzed. Overall trends in serum TC and LDL levels differed between ICH subjects and non-ICH controls (p<0.0001). ICH subjects experienced significant decline in serum TC and LDL levels during 6 months immediately preceding ICH, compared with levels between 6 to 24 months pre-ICH (TC: -29.25mg/dL, p=0.001; LDL: -21.48mg/dL, p=0.0038), which were not observed in non-ICH controls (TC: -4.32mg/dL, p=0.41; LDL: -1.56mg/dL, p=0.85). Subgroup analysis confirmed that this phenomenon could not be attributed to statin or alcohol exposure. Trends for serum TG and HDL did not differ between groups. Conclusions: Longitudinal serum TC and LDL levels demonstrate decline within 6 months preceding primary ICH, independent of statin or alcohol use. Subjects hospitalized for non-cerebral events did not exhibit this phenomenon. These temporal trends suggest changes in serum TC and LDL levels herald a generalized process that may precipitate ICH occurrence. Further studies are needed to replicate these results and characterize rate of change in serum lipids as a potential biomarker of impending acute cerebral injury.

Background and purpose Blood pressure reduction is a promising intervention for acute intracerebral hemorrhage, but clinical trials of this treatment often exclude those with anticoagulant-associated intracerebral hemorrhage, leaving it unclear whether this population might benefit. We examined whether persistently elevated blood pressure values (blood pressure burden) over the first 24h are associated with hematoma expansion and mortality in anticoagulant-associated intracerebral hemorrhage.Methods We retrospectively identified consecutive patients with primary anticoagulant-associated intracerebral hemorrhage (warfarin anticoagulation) who presented within 6h after symptom onset and a matched set of non-anticoagulant-associated intracerebral hemorrhage patients. Associations between 24h blood pressure burden, hematoma expansion, and mortality were evaluated using univariable and multivariable logistic regression.Results Sixty-nine anticoagulant-associated intracerebral hemorrhage and 69 matched non-anticoagulant-associated intracerebral hemorrhage patients were included. Hematoma expansion occurred in 25 anticoagulant-associated intracerebral hemorrhage patients (36%) and 15 control patients (22 %; p=0.091). Twenty-four-hour blood pressure burden was in fact lower in anticoagulant-associated intracerebral hemorrhage than in non-anticoagulant-associated intracerebral hemorrhage patients (p=0.033). No association was found in anticoagulant-associated intracerebral hemorrhage and non-anticoagulant-associated intracerebral hemorrhage between BP burden, hematoma expansion, and 30-day mortality.Conclusion We found no evidence that higher 24h blood pressure burden is associated with hematoma expansion or mortality in anticoagulant-associated intracerebral hemorrhage.

Although maltreatment is a known risk factor for multiple adverse outcomes across the lifespan, its effects on cognitive development, especially memory, are poorly understood. Using data from a large, nationally representative sample of young adults (Add Health), we examined the effects of physical and sexual abuse on working and short-term memory in adulthood. We examined the association between exposure to maltreatment as well as its timing of first onset after adjusting for covariates. Of our sample, 16.50% of respondents were exposed to physical abuse and 4.36% to sexual abuse by age 17. An analysis comparing unexposed respondents to those exposed to physical or sexual abuse did not yield any significant differences in adult memory performance. However, two developmental time periods emerged as important for shaping memory following exposure to sexual abuse, but in opposite ways. Relative to non-exposed respondents, those exposed to sexual abuse during early childhood (ages 3-5), had better number recall and those first exposed during adolescence (ages 14-17) had worse number recall. However, other variables, including socioeconomic status, played a larger role (than maltreatment) on working and short-term memory. We conclude that a simple examination of "exposed" versus "unexposed" respondents may obscure potentially important within-group differences that are revealed by examining the effects of age at onset to maltreatment.

Objective: We sought to determine whether APOE genotype influences a previously observed decline in serum total cholesterol (TC) and low-density lipoprotein (LDL) levels preceding primary intracerebral hemorrhage (ICH), as a potential demonstration of nonamyloid mechanisms of APOE in ICH risk.Methods: We performed a single-center retrospective longitudinal analysis using patients with known APOE genotype drawn from an ongoing cohort study of ICH. Serum lipid measurements for TC, triglycerides (TGs), LDL, and high-density lipoprotein (HDL) collected within 2 years before and after index ICH were extracted from electronic medical records. Piecewise linear mixed effects models were used to compare APOE allele-specific effects on temporal serum lipid trends in ICH. Demographics, medical history, medications, and health maintenance data were included as fixed effects. Inter- and intraindividual variations in lipid levels were modeled as random effects.Results: A total of 124 ICH cases were analyzed. APOE epsilon 4 carriers had greater rates of decline in serum TC and LDL within 6 months preceding ICH (TC: -7.30 mg/dL/mo, p = 0.0035; LDL: -8.44 mg/dL/mo, p - 0.0001). Conversely, serum TC and LDL levels in APOE epsilon 2 carriers were unchanged within the same time period. APOE genotype had no associations with serum HDL or TG trends.Conclusions: APOE allele status predicts serum TC and LDL changes preceding acute ICH. Our results have implications for ongoing efforts in dissecting the role of dyslipidemia in cerebrovascular disease risk. APOE genotype-specific influence on lipid trends provides a clue for one mechanism by which APOE may influence risk of ICH. Further characterization of the metabolic roles of APOE is needed to improve the understanding of APOE biology in cerebrovascular disease risk.

OBJECTIVE: To investigate the relationship between APOE polymorphism and plasma lipid concentration in patients with primary intracerebral hemorrhage (ICH) BACKGROUND: Apolipoprotein E (APOE) plays a role in lipid metabolism and variants are associated with increased total cholesterol (TC) and Low-Density Lipoprotein (LDL) in genome-wide association studies (GWAS) of lipid levels. The APOE e4 allele has also emerged as a leading genetic risk factor for ICH. However, multiple observational and randomized-controlled studies suggest an association between hypercholesterolemia and reduced risk of ICH. We investigated the influence of APOE e4 polymorphism on plasma lipid profile in patients with primary ICH. DESIGN/METHODS: We performed a retrospective analysis of 306 patients with primary ICH (148 lobar and 158 deep), aged more than 18 years old, enrolled in a prospective single-center study of ICH between July 1, 1994, and July 1, 2014 with known APOE genotype status as well as plasma lipid panel data available via the electronic medical record within 2 years prior to their ICH. Demographic variables, medical and medication histories including statin use, were captured from a baseline interview. RESULTS: Among primary ICH cases, APOE e4 carriers had significantly increased levels of plasma TC and LDL levels compared with non-APOE e4 carriers (p=0.0086 and p=0.0033, respectively). The association remained significant even after adjustments for age, gender, race, diabetic status, and statin use. Presence of the e4 allele increased TC and LDL levels by 11.6 mg/dL (p=0.039) and 11.8 mg/dL (p=0.016), respectively. CONCLUSIONS: APOE e4 increases both plasma TC and LDL levels in patients with primary ICH, consistent with the biological effects seen in population-level GWAS of lipid traits. Future studies are needed to further characterize the lipid-dependent and independent roles of APOE in cerebrovascular disease.

Objective: Genetic variants ε2/ε4 within the APOE gene are established risk factors for lobar intracerebral hemorrhage (ICH). Published preliminary data suggest a potential role for APOE ε4 in risk of nonlobar ICH. We therefore investigated the role of APOE in recurrent nonlobar ICH, and sought to clarify whether effects of APOE on circulating lipids mediate this association. Methods: Three hundred sixty-three survivors of nonlobar ICH were followed prospectively for ICH recurrence, with APOE genotype determined at enrollment. All participants had clinical, demographic, and laboratory data captured at time of index ICH and during follow-up. Using a multivariate model, we performed association and interaction analyses of the relationships among APOE genotype, lipid levels, and recurrent nonlobar ICH. Results: We observed 29 nonlobar ICH recurrences among 363 survivors. APOE ε4 was associated with recurrent nonlobar ICH (hazard ratio = 1.31; 95% confidence interval = 1.02–2.69; p = 0.038) after adjustment for age/sex/ethnicity and cardiovascular risk factors. Increasing low-density lipoprotein (LDL) levels were associated with decreased risk of recurrent nonlobar ICH (p = 0.027), as were decreasing HDL levels (p = 0.046). LDL levels modified the association of APOE ε4 with recurrent nonlobar ICH (mediation p < 0.05). No associations were identified between APOE ε2 and recurrent nonlobar ICH. Conclusion: APOE ε4 is associated with recurrent ICH in nonlobar brain regions, providing further evidence for its causal role in ICH unrelated to cerebral amyloid angiopathy. LDL levels modulated this effect, suggesting that circulating lipid levels may mediate a portion of the role of APOE ε4 in nonlobar ICH.

Introduction: Genetic variants ε2 / ε4 within the APOE gene are established risk factors for lobar intracerebral Hemorrhage (ICH) and its recurrence. Data from a large case-control meta-analysis suggest a potential but not yet replicated role for APOE ε4 in risk of non-lobar ICH. Hypothesis: APOE ε4 increases risk of recurrent non-lobar ICH and, replicating prior results, increases risk of initial non-lobar ICH. Methods: Among consecutive non-lobar ICH cases from our single center series (n=468), 363 survivors were followed for recurrence. All subjects had clinical and demographic data, and APOE genotype determined at the time of index ICH. In a separate case-control analysis, 156 non-lobar ICH cases and 152 ICH-free controls, ascertained subsequent to all prior publications, were analyzed as replication of previously published case-control findings. These case-control results were then meta-analyzed with previously published data. Results: We observed 29 non-lobar-ICH recurrences among 363 survivors. APOE ε4 was associated with non-lobar-ICH recurrence (HR = 1.31, 95% CI =1.02 - 2.69, p = 0.038) after adjustment for age / gender / ethnicity and cardiovascular risk factors. Case-control analyses of newly ascertained subjects replicated the APOE ε4 association with risk of non-lobar ICH (OR = 1.31, 95% CI = 1.02-1.68, p = 0.035). Meta-analysis of these with published case-control data returned an association between ε4 and non-lobar ICH (OR = 1.21, 95% CI = 1.11-1.32, p = 1.5 x 10 -5 ). No associations were identified between APOE ε2 and non-lobar ICH risk or recurrence. Conclusions: APOE ε4, but not ε2 is associated with risk and recurrence of non-lobar ICH. Whether APOE’s role in non-lobar ICH involves beta-amyloid pathology, its presumed mechanism in lobar ICH, requires further study.