Jonathan Rosand - US grants

DESCRIPTION (provided by applicant): Intracerebral hemorrhage (ICH), bleeding into brain parenchyma from an arterial source, is the deadliest form of stroke and, in contrast to ischemic stroke, lacks any well-proved effective therapy. Although the majority of cases of ICH are spontaneous, ICH is also the most feared complication of warfarin, a medication indicated for long-term use in millions of Americans with atrial fibrillation. When associated with warfarin, ICH is even more devastating, with fatality over 50%. This research program aims to identify the genetic predictors of outcome from ICH and from ICH specifically related to warfarin. It will investigate apolipoprotein E genotype (APOE) and the factor XIII Val34Leu polymorphism. The objectives of this proposal are to determine 1) whether APOE predicts large hematoma volume in acute ICK, acute hematoma enlargement, and poor clinical outcome from acute ICH, and 2) whether factor XIII Val34Leu predicts hemorrhage recurrence in survivors of ICH, and is an independent protective factor for outcome from ICH related to warfarin. These objectives will be completed in a carefully characterized cohort of consecutive cases of spontaneous ICH. Because of the rapid growth in the understanding of both the human genome and the molecular basis of coagulation and vessel pathology, this cohort is likely to form the foundation of a powerful, open-ended search for genetic determinants of ICH and serve as a crucial tool for future studies. During the award period, in addition to serving as principal investigator for the proposed studies, Dr. Rosand will complete formal didactic training in research ethics, epidemiology, and biostatistics with a focus on the statistics applied to genetic studies of complex diseases. His mentor will be Dr. Steven M. Greenberg. Drs. James F. Gusella and Walter J. Koroshetz will serve as co-mentors. Upon conclusion of the award, Dr. Rosand, who has completed clinical fellowship training in stroke and critical care neurology, will have acquired the requisite skills to function as an independent investigator with specific expertise in genetic epidemiology. He will be trained to conduct fundamental studies in clinical and molecular epidemiology of acute cerebrovascular disease as well as pivotal clinical trials of novel therapeutic interventions for ICH.

Intracerebral hemorrhage (ICH) is the deadliest stroke subtype. Warfarin, a widely used anticoagulant for prevention of thromboembolic stroke, increases both risk and severity of ICH. Thus, even relatively minor elevations in risk for ICH on warfarin can sway the balance in favor of withholding treatment. Accumulated evidence points to a strong familial contribution to ICH susceptibility. Data from the investigators suggest warfarin-related ICH shares genetic risk factors with ICH in individuals not on warfarin. The identification of genetic risk factors for ICH may therefore offer novel biological insights, as well as provide immediate clinical impact by improving risk assessment for chronic anticoagulation. To discover genes involved in development of ICH and warfarin-related ICH, this proposal brings together a team of clinician-investigators with world-class expertise in the phenotyping and biology of ICH alongside geneticists who are among the world's preeminent experts in the methods and analysis of genome-wide data. The population of patients who will contribute are the most thoroughly characterized ICH cases and controls available, and have been assembled specifically for genetic and gene-environment studies. Subjects all have detailed data on warfarin dose, laboratory values including coagulation parameters, clinical history, neuroimaging and clinical follow-up. Specific aims are:1) To collect and curate data for >900,000 SNPs and 946,000 copy number probes in 1,000 cases with ICH unrelated to warfarin and 1,000 matched controls not taking warfarin; 2) To identify genetic variants associated with warfarin-related ICH, using data for >900,000 SNPs and 946,000 copy number probes in 500 cases of warfarin- related ICH and 1,000 matched controls taking warfarin, but without ICH; 3) To identify genetic variants that influence warfarin dose requirement in the same group of 500 cases of warfarin-related ICH and 1,000 matched controls. Replication of any association will be carried out in three additional independent datasets. Our study will thoroughly test the hypothesis that common variants play a major role in ICH, setting the stage for the future genetic study of this disease. The team's track record of cutting-edge research in the neuroimaging and epidemiology of ICH as well as in human genetic variation, along with our aggressive data release policy, will ensure that the substantial investment in phenotyping and genotyping is used for the widest possible benefit for present and future patients. Intracerebral hemorrhage (ICH) is the deadliest stroke subtype. Warfarin, a widely used anticoagulant for prevention of thromboembolic stroke, increases both risk and severity of ICH. This project aims to discover the genes that cause ICH in individuals on and off warfarin. It therefore offers the promise of novel biological insights, as well as immediate clinical impact through improving risk assessment for chronic anticoagulation.

The overall goal of our fellowship training and career development program is to develop a generation of clinician-scientists committed to careers in translational acute stroke research. Consistent with the vision detailed in the RFA (PAR-09-254), the training program will provide career development opportunities for new investigators who wish to pursue active research careers in translational acute stroke research. Drawing its fellows locally, from individuals trained in the Massachusetts General Hospital-Brigham and Women's Hospital/Harvard Medical School Training Programs in Emergency Medicine (residency), Neurology (residency) and Vascular Neurology (fellowship), as well as nationally, and internationally, the Partners SPOTRIAS Fellowship Training Program will provide a focused mentored full-time one-year research experience with the goals of obtaining advanced training in research methods and preparing strong applications for independent funding for future research career-development. Aim 1: To select and train promising candidates for independent careers (academic, industrial, governmental) in translational stroke research Aim 2: To train SPOTRIAS research fellows who secure independent research funding for future career development

DESCRIPTION (provided by applicant): Intracerebral hemorrhage (ICH), bleeding into the brain from a ruptured blood vessel, remains the most devastating stroke subtype, with 30-day mortality approaching 40% and severe functional impairments in the majority of survivors. The amount of blood that exits the ruptured vessel is the most powerful determinant of outcome in ICH, and while there are currently no proven treatments for acute ICH, the observation that continued bleeding and hematoma growth commonly occur points to an inviting therapeutic target. Two interventions (hemostatic and antihypertensive therapy) appear to slow hematoma growth, but this reduced expansion has thus far failed to translate into clinical benefit in clinical trials. These observations underscore the importance of clarifying the relationship between hematoma expansion and clinical outcome. Motivating the current proposal is the idea that improved predictive markers and biological characterization of hematoma growth will lead to efficient, personalized selection of optimal therapy. The goal of this approach is to target treatment to patients at highest risk for expansion and likeliest to respond to a specific therapy. We focus on two neuroimaging markers characterized by our group and others: 1) pooling of contrast or spot sign on contrast CT angiography (CTA), a widely used extension of the standard emergency head CT; and 2) demonstration of cerebral microbleeds (CMB) on sensitive T2*-weighted MRI sequences, also part of the routine diagnostic evaluation of acute ICH. Accumulating evidence strongly supports CTA spot sign findings as powerful predictors of likelihood of expansion. Data from MRI imaging, though less definitive, also implicate CMB as markers of microvascular structure and associated risk of hematoma growth. As these two methods detect distinct aspects of ICH pathogenesis, our expectation is that they will provide complementary biological and predictive information regarding risk of expansion. Our overall goal is to apply CTA and MRI to identify patients at highest risk for hematoma expansion. Partnering with the Antihypertensive Treatment in Acute Cerebral Hemorrhage-2 (ATACH-2) trial, we will determine whether CTA and MRI can identify patients at high risk for hematoma growth and whether these imaging techniques can select patients more likely to benefit from early, intensive antihypertensive treatment. Our proposal takes advantage of three specific factors: 1) the tremendous leverage obtained from building on the wealth of data to be collected in ATACH-2, 2) the widespread use of CTA and T2*-weighted MRI by tertiary stroke centers in the clinical evaluation of ICH (thus necessitating no separate consent process for enrollment in our substudy), and 3) our research group's widely recognized expertise in the interpretation of both of these techniques. Successful completion of the proposed studies will be a major step towards optimizing the application of current and future approaches to hematoma growth and establishing tangible improvements in ICH outcome.

? DESCRIPTION (provided by applicant): Despite substantial advances in its treatment and prevention, stroke remains the second-leading cause of death worldwide and the leading cause of major disability among adults. Identifying the biological processes that underlie the cerebrovascular diseases that cause stroke is crucial to guiding the development of safe and effective therapies. The dramatic fall in cost of genome-wide genotyping and sequencing has made it possible to systematically collect vast amounts of data on individual genome variation. In parallel with advances in genotyping and sequencing technology, there has been a substantial increase in the availability and complexity of data characterizing patients. Neuroimaging, via CT and often MRI, is very frequently obtained during routine clinical evaluation and classification of stroke subtype can now be comprehensively ascertained using online tools that require and retain large amounts of primary data from medical evaluations. Finally, electronic medical records now retain increasing amounts of data on patients enrolled in research studies. By generating and analyzing genome-wide genotypes and collecting and analyzing extensive imaging and phenotype data in thousands of individuals with stroke, the International Stroke Genetics Consortium (ISGC) has made substantial progress in identifying the genetic variants that influence risk of stroke, the initial step in the discovery cycle. Nonetheless, substantial barriers remain to leveraging these and future data for the advancement of our understanding of cerebrovascular disease and the ultimate development of novel therapeutic targets for stroke. Datasets are (1) of unprecedented scale, (2) disparate in location, and (3) heterogeneous in type. As a result, the research community lacks the data access and integration necessary in order to perform valid and well-powered comparisons to generate new hypotheses and improve our understanding of cerebrovascular disease biology. We propose to create new infrastructure for the wide sharing of human genetic, phenotypic and neuroimaging data for the purpose of accelerating the search for effective treatments for cerebrovascular disease. The Platform for accelerating genetic discovery for cerebrovascular disease will overcome these three barriers by creating a flexible and scalable resource for the investigative community that integrates genetic datasets containing individual-level genotyping results, incorporating over 30,000 stroke cases and appropriate stroke- free controls collected from dozens of centers around the world, all having undergone centralized quality control according to a single streamlined approach, and all made available through an ethics committee- approved process for rapid sharing with any investigator world-wide. Governed by a steering committee made up of long-standing collaborators in stroke genetics, this resource will transform the genetic study of stroke in humans, providing a durable resource that can ultimately be sustained by the established collaborative culture of the ISGC and small subsidies from researchers who utilize the Platform

? DESCRIPTION (provided by applicant): Cerebral small vessel disease (CSVD) is a common, progressive condition of aging, and a leading contributor to age-related disability due to stroke, cognitive decline, late-life onset depression and gait deterioration. In most cases the underlying vessel pathology can be classified as one of the two most common subtypes, arteriolosclerosis (AS) and cerebral amyloid angiopathy (CAA). Although classically recognized as white matter changes on MRI, CSVD frequently comes to clinical attention for the first time when a patient presents with intracerebral hemorrhage (ICH). Discovering the biological underpinnings of CSVD is a vital next step toward development of effective preventative strategies. Because their CSVD is uniformly severe, ICH survivors are ideal subjects in which to study CSVD and also form the group most likely to benefit from novel therapies. The proposed studies are motivated by the striking observation that ICH disproportionately affects African- American (AA) and Hispanic-American (HA) populations. Our preliminary analyses demonstrate that these differences extend to post-ICH risk for recurrent ICH, cognitive decline and late-life depression and that blood pressure (BP) may play a fundamental role in these differences. Our revised proposal, best titled Longitudinal Follow-up of ICH Survivors in ERICH, will systematically determine whether 1) AA and HA are predisposed to CSVD of all types, 2) are predisposed solely to increased risk of AS, or 3) have no inherent predisposition but, through the effects of BP suffer more severe CSVD. To test the central hypothesis that discovering the mechanisms for this health disparity ICH will yield biological insights for CSVD, advance the search for treatments and have impact at the bedside, we propose to leverage the soon- to-conclude Ethnic/Racial Variations of ICH (ERICH) study to perform longitudinal follow-up of a cohort of 900 ICH survivors (300 each of AA, HA, and NHW), recruited in the last two years of ERICH, who have had neuroimaging, genetic, epidemiologic, and socio-ethnic variables ascertained at time of enrollment. Subjects will be followed by telephone every 6 months according to established and validated protocols.

Project Summary We seek support for a postdoctoral training program in Recovery and Restoration of Brain Health and Function following acute brain injury due to stroke or trauma to be administered by the Department of Neurology at Massachusetts General Hospital. Combining the expertise of the clinical neurosciences at MGH and the Brown Institute for Brain Science at Brown University, this program will fill a pressing need for clinician-scientists and neuroengineers trained to leverage the computational neurosciences and to develop device-based interventions on behalf of patients who survive disabling brain injuries. The program will involve active participation by an accomplished, experienced, and multidisciplinary training faculty drawn from anesthesia, bioengineering, computational neuroscience, neurology, neurosurgery, physical medicine and rehabilitation, psychiatry, and radiology. The program will train postdoctoral clinician-scientists who have an understanding of and commitment to research in functional recovery and will devote themselves to studying the effects of novel interventions in patients. Postdoctoral neuroengineers trained by the program will be integrated into clinical research teams so that they can gain an understanding of the clinical environment required to lead multi- disciplinary teams developing new treatments for patients who survive brain injuries. Mentors and research experiences cover five overarching themes: 1) Clinical research and clinical trials, 2) Computational neuroscience, 3) From neural recording to neural imaging, 4) Neural repair, and 5) Neuromodulation. Trainees will spend a minimum of two years in the program. The program will combine a mentored research project within one of the five theme areas with specific coursework tailored to the theme area chosen by the trainee. All trainees will enroll in career development training activities specifically tailored to their background as clinician or neuroengineer. At its completion they will be prepared to submit successful research career development awards devoted to improving outcomes for survivors of acute brain injury. The program will capitalize on 1) strong clinical training programs in acute brain injuries at MGH, 2) strong research training programs in the clinical neurosciences, 3) strong bioengineering and computational neuroscience research training programs at Brown, and 4) the already close collaboration between MGH and Brown.