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Report of the Stroke Progress Review Group - April 2002
Table of Contents
About the Stroke Progress Review Group
Executive Summary- Scientific Session Reports: Full Reports of the Stroke Progress Review Group
Roundtable Meeting Breakout Sessions - Cerebrovascular Biology
Neuro/Cerebrovascular Degeneration
Healing Process of Stroke
Neurovascular Protective Mechanisms
CNS Thrombosis and Hemorrhage
Vascular Dementia
Genetics
Defining Disease I (Genomics/Proteomics)
Defining Disease II (Imaging)
Epidemiology and Risk Factors
Prevention of First and Recurrent Stroke
Acute Stroke Treatment
Clinical Trials
Recovery and Rehabilitation
Health Services Implementation
Message From the Director
It is my pleasure to share with you this Report of the Stroke Progress Review Group (SPRG).
Over the last few years, the National Institute of Neurological Disorders and Stroke (NINDS) has embarked on a strategic planning process to identify scientific opportunities that have the potential to significantly advance the fields of neuroscience and neurology and to address unmet scientific needs that may limit that potential. Our initial efforts resulted in the publication of our first strategic plan, Neuroscience at the New Millennium in 1999. In addition to this general plan, which continues to provide a framework for the Institute's initiatives, NINDS has also recently undertaken planning efforts in specific areas, such as Parkinson's disease, brain tumor, epilepsy, and health disparities research. These efforts have come about as a result of scientific opportunity and need, as well as Congressional and public interest.
The SPRG had its origins in Fiscal Year 2001 report language from the House and Senate Appropriations Committees to the NINDS urging us to develop a national research plan for stroke. Following on the success of the Brain Tumor Progress Review Group, a joint collaboration between NINDS and the National Cancer Institute to identify priorities for research on brain tumors, NINDS decided to use a Progress Review Group to develop a plan for stroke research.
The SPRG consists of prominent scientists, clinicians, patient advocates, and industry representatives who were chosen for both their expertise and their ability to think broadly. The SPRG was charged by NINDS with identifying and prioritizing the scientific needs and opportunities required to advance the stroke research field, and developing a research plan that addresses these opportunities and needs. This report is the culmination of their efforts, and outlines both research and resource priorities in fifteen areas of basic, translational and clinical stroke research.
The report has been presented to and approved by the National Advisory Neurological Disorders and Stroke Council, and will serve as a framework for the Institute's activities in stroke research over the next five to ten years. We look forward to working closely with the SPRG, together with the larger stroke research and patient communities, to advance the research field towards a better understanding of the etiology and pathophysiology of stroke and the development of more effective methods of both preventing strokes before they occur and treating them when they do.
Sincerely,
Audrey S. Penn, M.D.
Acting Director, NINDS
Foreword
This report represents the collaborative effort of scientists, clinicians, industry representatives, and patient advocates who were charged by the National Institute of Neurological Disorders and Stroke with the task of setting overall priorities for stroke research.
The executive summary of the report outlines those priorities in light of the biological and clinical complexity of stroke and the formidable challenges that have slowed progress toward effective treatments. Many priorities and directions need to be pursued in stroke research, and they are discussed in detail in the breakout session reports. Common themes emerged from those reports, however, and the Stroke Progress Review Group considers the priorities delineated in the executive summary to be the best guide to the future direction of stroke research.
This report and additional related information are available at the Stroke Progress Review Group web page on the National Institute of Neurological Disorders and Stroke web site (www.ninds.nih.gov).
TopAcknowledgments
The Report of the Stroke Progress Review Group (SPRG) is the product of work carried out over the past several months by the SPRG, the participants at the SPRG Roundtable Meeting, and staff of the National Institute of Neurological Disorders and Stroke (NINDS). The report is based on meetings of the SPRG leadership in Bethesda, Maryland, in October 2000; of the SPRG members in Crystal City, Virginia, in March 2001; of the Roundtable Meeting participants in Denver, Colorado, in July 2001; and of weekly conference calls of the SPRG leadership and NINDS staff throughout 2001.
Special thanks are extended to the NINDS Office of Science Policy and Planning for their extraordinary organization in all phases of the SPRG process. In particular, the guidance of Dr. Paul A. Scott, Dr. Melinda Kelley, and Ms. Patricia Turner has been invaluable. The dedication of Ms. Susie Nelson, of MasiMax, Inc., has been inspiring. The completion of the report was also greatly facilitated by Ms. Catherine Dold, who served as lead science writer, and by the breakout session reports prepared by Ms. Dold and the other expert science writers (Ms. Christie Aschwanden, Ms. Martha Engstrom, Ms. Vonne Sieve, Ms. Elizabeth Staton, and Dr. Linda White) at the Denver Roundtable Meeting.
Particular thanks are also due to the co-chairs of the Roundtable Meeting breakout sessions, who worked diligently with the SPRG members and participants to plan the breakout sessions and prepare the individual breakout session reports.
Finally, the SPRG recognizes the tremendous efforts of the stroke patient advocacy groups in supporting the NINDS in developing the SPRG process, and their invaluable participation in many aspects of the work.
TopFrom the Leadership
We are pleased to submit this Report of the Stroke Progress Review Group (SPRG) to the Director and National Advisory Neurological Disorders and Stroke Council of the National Institute of Neurological Disorders and Stroke (NINDS). In their FY2001 Appropriations Committee Report language, both the House of Representatives and the Senate directed NINDS to develop a national plan for both basic and clinical stroke research. At the beginning of 2001, the SPRG accepted this charge from Dr. Gerald Fischbach, Director of the NINDS, and moved quickly to develop an appropriate plan. The expertise and efficiency of the SPRG members and of the participants of the Roundtable Meeting have produced this exciting report in less than a year, reflecting the energy and enthusiasm of the clinical, research, industrial, and advocacy communities for identifying effective treatments for stroke.
The Report of the Stroke Progress Review Group highlights the scientific research priorities that represent the next steps toward understanding the biological basis of stroke and developing effective therapies for stroke. We look forward to discussing these priorities with the leadership of the NINDS.
James C. Grotta, M.D.Co-Chair, SPRG
Michael A. Moskowitz, M.D
Co-Chair, SPRG
Thomas P. Jacobs, Ph.D.
John Marler, M.D.
Katherine Woodbury-Harris, Ph.D.
Barbara Radziszewska, Ph.D.
Paul A. Scott, Ph.D.
Members of the Stroke Progress Review Group
SPRG Co-Chairs
James C. Grotta, M.D.
University of Texas
Health Science Center at Houston
Michael A. Moskowitz, M.D.
Harvard Medical School
Joseph S. Beckman, Ph.D.
Oregon State University
Eric Boerwinkle, Ph.D.
University of Texas
Health Science Center at Houston
Joseph P. Broderick, M.D.
University of Cincinnati
College of Medicine
Thomas G. Brott, M.D.
Mayo Clinic, Jacksonville
Pak H. Chan, Ph.D.
Stanford University School of Medicine
Bruce M. Coull, M.D.
University of Arizona
College of Medicine
Gregory J. del Zoppo, M.D.
The Scripps Research Institute
John Detre, M.D.
University of Pennsylvania Hospital
Pamela W. Duncan, Ph.D., P.T.
University of Kansas Medical Center
J. Donald Easton, M.D.
Brown Medical School
Giora Z. Feuerstein, M.D., M.Sc.
DuPont Pharmaceutical Company
Karen L. Furie, M.D., M.P.H.
Harvard Medical School
Meighan Girgus
American Stroke Association
Philip B. Gorelick, M.D., M.P.H.
Rush Medical Center
David Greenberg, M.D., Ph.D.
Buck Institute for Age Research
John M. Hallenbeck, M.D.
National Institute of Neurological Disorders and Stroke
Robert G. Hart, M.D
University of Texas
Health Science Center at San Antonio
Donald Heistad, M.D.
University of Iowa
George Howard, Dr.P.H.
University of Alabama, Birmingham
Costantino Iadecola, M.D.
University of Minnesota
Thomas P. Jacobs, Ph.D.
National Institute of Neurological Disorders and Stroke
Patrick D. Lyden, M.D.
University of California, San Diego School of Medicine
John R. Marler, M.D.
National Institute of Neurological Disorders and Stroke
David B. Matchar, M.D.
Duke University Medical Center
Lewis B. Morgenstern, M.D.
University of Texas
Houston Medical School
Randolph J. Nudo, Ph.D.
University of Kansas Medical Center
William J. Powers, M.D.
Washington University School of Medicine
Barbara Radziszewska, Ph.D.
National Institute of Neurological Disorders and Stroke
Ralph L. Sacco, M.D., M.S.
Columbia University Neurological Institute
Timothy J. Schallert, Ph.D.
University of Michigan
Paul A. Scott, Ph.D.
National Institute of Neurological Disorders and Stroke
Frank R. Sharp, M.D.
University of Cincinnati Medical Center
Patti Shwayder
National Stroke Association
Roger P. Simon, M.D.
Robert S. Dow Neurobiology Laboratories
Richard J. Traystman, Ph.D.
The Johns Hopkins University School of Medicine
Bryce Weir, M.D.
University of Chicago
Philip A. Wolf, M.D.
Boston University School of Medicine
Katherine Woodbury-Harris, Ph.D.
National Institute of Neurological Disorders and Stroke
Justin A. Zivin, M.D., Ph.D.
University of California, San Diego
Top
About the Stroke Progress Review Group
The National Institute of Neurological Disorders and Stroke (NINDS) is the nation's leading supporter of biomedical research on disorders of the brain and nervous system, and supports basic, clinical, and population-based research to identify and study the causes, biology, prevention, early detection, and treatment of stroke. Through years of dedicated study, researchers supported by the NINDS have amassed a significant knowledge base about stroke, and this knowledge, coupled with new technologies, is providing a wealth of new scientific opportunities. At the same time, increasing research needs and scientific opportunities require that the NINDS determine the best uses for its resources. It is necessary to identify clear scientific priorities, both to provide guidance for the scientific community and to create a benchmark against which progress can be measured.
The Stroke Progress Review Group (SPRG) was convened to identify those priorities. It is modeled after the National Cancer Institute's (NCI) planning process, which was originally established to assist the NCI in assessing the state of knowledge and identifying scientific opportunities and needs within its large, site-specific research programs. The SPRG follows on the success of the Brain Tumor Progress Review Group (BT-PRG), which was jointly established in 2000 by NINDS and NCI in recognition of the importance of brain tumor research to both institutes.
CHARGE TO THE STROKE PROGRESS REVIEW GROUP
The Stroke Progress Review Group was charged with assisting the NINDS in addressing the needs of the institute's stroke research program. SPRG members were asked to take a broad view in identifying and prioritizing unmet scientific needs and opportunities that are critical to the advancement of the research field. The SPRG was specifically charged with the following goals:
- Identify and prioritize scientific research opportunities and needs, and the scientific resources needed to address them, to advance medical progress.
- Compare and contrast these priorities with an NINDS-prepared analysis of its stroke research portfolio.
- Develop a research plan of action that addresses unmet opportunities and needs.
- Prepare a written report describing the SPRG's findings and recommendations, for deliberation by the National Advisory Neurological Disorders and Stroke Council.
This report is the final product of the SPRG's efforts and deliberations, and it describes the group's findings and recommendations for advancing stroke-related research. The following sections detail the process used in producing this report.
THE STROKE PROGRESS REVIEW GROUP PROCESS
The SPRG members include prominent scientists, clinicians, consumer advocates, and industry representatives from the United States and Canada who together represent the full spectrum of scientific expertise needed to make comprehensive recommendations for the NINDS stroke research agenda. Members were selected for their expertise as well as their ability to take a broad view in identifying and prioritizing the scientific needs and opportunities that are critical to advancing the field of stroke research.
In February 2001, the SPRG leadership finalized an agenda and process for the SPRG Planning Meeting. At the Planning Meeting, held in March 2001, additional members of the stroke community were identified and invited to participate in a later Roundtable Meeting. Topics were identified for Roundtable Meeting breakout sessions, and all participants were assigned to attend particular sessions. The SPRG members were assigned to co-chair the breakout sessions.
The SPRG Roundtable Meeting, held in July 2001, brought together approximately 140 leading members of the stroke research and advocacy communities, representing diverse institutions and scientific disciplines. These experts met in an open forum (both as a large group and in smaller breakout sessions) to formulate the key scientific questions and priorities for the next five to ten years of stroke research. The NINDS provided the Roundtable Meeting participants with extensive information about their research programs for use in their review. The research priorities and resource needs that the Roundtable Meeting participants identified in the course of their deliberations are outlined in this report.
DEVELOPMENT OF THE SPRG REPORT
After the Roundtable Meeting, an intermediate draft of this report was prepared, and multiple iterations were reviewed by the SPRG leadership and SPRG members. Upon completion of the final draft, the report was submitted for deliberation and acceptance by the NINDS Advisory Council. The report will be widely disseminated and integrated into the institute's planning activities. The SPRG will meet with the NINDS director to discuss the institute's response to the report.
TopExecutive Summary
INTRODUCTION
The Stroke Progress Review Group (SPRG) occurs at a critical juncture for the field of stroke research. We have enjoyed wonderful progress during the past "Decade of the Brain." Highlights have included a number of successful large-scale clinical trials that have enabled physicians to make evidence-based decisions regarding stroke prevention and treatment. Even better, these trials have provided us with effective therapies to reduce the risk of stroke, prevent recurrent stroke, and reduce damage in the first minutes after a stroke has occurred. We have developed sophisticated imaging techniques that enable us to diagnose stroke and its pathogenic mechanisms rapidly and precisely. We have made substantial progress in unraveling the complex cascade of hemodynamic, biochemical, and molecular changes that occur in response to ischemic injury. And we have learned about differences in stroke incidence and outcome in various populations, stimulating current research to understand these epidemiologic trends on genetic, behavioral, and lifestyle levels.
Despite this progress, the challenge to make new strides in stroke research is more urgent than ever. From a public health perspective, stroke is the third leading cause of death in the United States, and a leading cause of long-term disability. With the aging of the population, the absolute number of stroke patients in the U.S. is likely to grow substantially. Stroke is also a significant burden on public health worldwide. Our understanding of the inherited basis of human disease is increasing dramatically, but the energy and focus of such genetic research has yet to be applied fully to stroke. Despite years of laboratory and clinical research, assessing the risk of stroke for individuals remains imprecise. Moreover, stroke is still difficult for non-specialists to diagnose, it is complicated to treat, and there are few effective therapeutic alternatives. Furthermore, too few medical graduates are choosing careers in laboratory or clinical stroke research to carry out the work that is needed to change this situation.
The purpose of the SPRG was to assemble the leaders in various areas of stroke research, as well as representatives of the stroke community, who could identify the current challenges and opportunities in the field. In the end, our goal was to lay out a broad menu of research priorities that might serve to both stimulate and guide stroke research over the next decade.
STRUCTURE AND PROCESS OF THE STROKE PROGRESS REVIEW GROUP
The SPRG identified 15 key areas of research activity in the field of stroke and brought together experts from the basic and clinical sciences, along with representatives from industry and the advocacy community, to discuss future goals for research in each area.
Because stroke research encompasses multiple and wide-ranging disciplines, experts from diverse backgrounds were invited to take part in the process; the participants included hematologists, vascular biologists, radiologists, clinical trialists, molecular biologists, geneticists, statisticians, vascular physiologists, adult and pediatric neurologists, neurosurgeons, neuroscientists, anesthesiologists, psychiatrists, behavioral scientists, and neuroepidemiologists. Two co-chairs were identified for each of the 15 research areas and asked to lead breakout discussion sessions. The participating experts were invited to take part in as many as three of the sessions.
In July 2001, all the SPRG participants met in Denver. During that meeting, each breakout session group met to identify their top three priorities for research focus and to highlight existing problems in their respective areas, barriers to this research, scientific goals, and the resources necessary to achieve these goals. The co-chairs then prepared documents summarizing each group's findings, along with their priorities. Those documents are found under Scientific Session Reports: Full Reports of the Stroke Progress Review Group Roundtable Meeting Breakout Sessions.
In reviewing the conclusions of the 15 breakout sessions, the members of the SPRG identified five broad Research and Scientific Priorities, as well as seven Resource Priorities needed to implement such research. These priorities have broad implications -- they apply to adult and pediatric patients, to individuals with ischemic or hemorrhagic stroke, and to underserved patient groups within the population. The sections that follow summarize the highlights of the Denver Roundtable Meeting and formulate the common themes heard in the sessions into a vision for the future of basic and clinical stroke research.
RESEARCH AND SCIENTIFIC PRIORITIES
The research priorities listed below represent a consensus of scientific goals expressed in many of the 15 breakout sessions. In order to satisfy these priorities and to successfully prevent and treat stroke in the future, each priority must be implemented by strong bi-directional interactions between basic and clinical stroke researchers. All of these priorities were considered equally important in accomplishing the overall goals of the PRG.
SCIENTIFIC PRIORITIES- Identify genes, mRNA, and proteins for ischemia, hemorrhage, and prevention
- Define blood/blood vessel wall/brain integrated function
- Understand blood flow regulation and perfusion optimization
- Develop combination therapies based on molecular and cellular pathways of injury
- Characterize remodeling and recovery after stroke
- Identify and isolate the genes, mRNA, and proteins underlying ischemic and hemorrhagic stroke, in order to provide an improved
fundamental biologic understanding of stroke epidemiology, prevention, diagnosis, and treatment.
There was universal agreement that the field of stroke is ripe for the genomic revolution that is now creating new and previously unimagined opportunities for diagnosis and treatment of neurological and other diseases.
Advances in mapping the human genome have recently made it feasible to identify and isolate genes that predispose individuals to ischemia and hemorrhage, to understand ways in which the encoded proteins modulate vascular physiology, and to recognize the cellular mechanisms of injury and death that can be initiated by stroke. For example, by identifying stroke-related genes, we can identify populations at risk with greater precision and develop more specific and effective measures for first and recurrent stroke prevention. Knowledge about the genes and proteins expressed during acute injury can help us to better classify and understand the natural history of human stroke subtypes, and to understand the biological basis for these subtypes. Furthermore, the pattern of genes expressed during stroke can be useful to detect the presence, time of onset, and extent of stroke in the emergency setting, thereby aiding physicians in diagnosing ischemia and hemorrhage more quickly and with greater accuracy. In addition, by knowing the patient's genetic profile, therapies can be individualized and tailored to variations in the genome that dictate the optimal response to specific drugs. Finally, once we identify and isolate the genes and proteins modulating responses to chronic injury and repair and determine how they work together, we may better understand the biological basis for recovery and rehabilitation and expand the limits of brain function after stroke.
- Study the interface between the brain's vasculature and cellular, matrix, and hemostatic mechanisms, to achieve a better understanding
of the events that lead to brain hemorrhage and infarction.
Extensive studies of neurons and glia have resulted in a detailed but still incomplete understanding of ischemic injury. If we are to understand, prevent, and treat stroke effectively, we need to investigate local hemostasis and its relationship to local tissue factors, microglia, endothelium, and the cells of the blood-brain barrier, including astrocytes. At a fundamental level, there is an important need to better define the molecular influences and cell-signaling mechanisms that characterize the interactions between circulating blood elements and the blood vessel wall, extracellular matrix, glia, and neurons (together, the neurovascular unit) during ischemic and hemorrhagic stroke. These interactions critically define events that initiate ischemia, hemorrhage, brain inflammation, blood-brain barrier dysfunction, and white matter changes after stroke. Progress in the prevention, diagnosis, and treatment of stroke will depend upon a critical understanding of these interactions.
To achieve this goal, the SPRG members recommended greater focus on the process of hemostasis, platelet and leukocyte function, and particularly, aspects of their interactions that are unique to the brain. This knowledge may be useful to identify potential therapeutic targets even more specific for stroke than for thrombotic events in other organs. The SPRG members also emphasized the importance of studying the extracellular matrix proteins that play a role in the development of hemorrhage, inflammation, and blood-brain barrier dysfunction after stroke. In addition to these proteins, the SPRG members highlighted the need to study glial cells and their role in blood-brain barrier integrity, synaptic and trophic functions, inflammation, and angiogenesis. Glia and matrix proteins are fundamental to white matter structure and function, and the white matter lesions that commonly develop after stroke can cause or contribute to vascular dementia. Finally, a study of the blood-vessel wall/matrix/glial interaction would be incomplete without an emphasis on stroke risk factors such as diabetes, hypertension, atherosclerosis, and obesity, and their impact on interactions within component cellular and acellular elements of the neuro-vascular unit. We do not have a full understanding of how these very common diseases modulate hemostasis and vessel wall structure and function to specifically place the brain at high risk for stroke.
- Understand blood flow and perfusion optimization.
The fundamental pathophysiology of stroke is caused by an interruption of blood flow. Building on our existing knowledge of cerebral blood flow and metabolism, we should explore emerging imaging technologies that will enable us to understand the regulation and restoration of blood flow after both ischemic and hemorrhagic stroke.
We need to better understand how to optimally reestablish flow in the macro- and microcirculation. One important approach will involve the amplification of existing acute ischemic stroke therapy by accelerating the testing of devices and new pharmacologic approaches to achieve reperfusion more quickly, more completely, and safely.
Reperfusing brain quickly can improve recovery, but reperfusion can also promote mal-adaptive responses. We need to understand the consequences of reperfusion at the molecular and cellular level so that tissue survival can be optimized in the reperfused brain.
Many clinical questions must be addressed. Among them:
- What are the effects on the endothelium of intra-arterial cannulation, drug infusion, and various ultrasonic and other energy-producing devices?
- What are the cellular and hemostatic events that cause arteries to bleed and to stop bleeding? Can we improve our efforts to prevent or limit bleeding?
- What determines the formation of thromboemboli in the cerebral circulation?
- Taking the lead from recent data in the coronary circulation, can we identify unstable plaques in the cerebral circulation?
- Can these investigations lead to more selective surgical and endovascular prevention, and more effective post-stroke thrombolysis and less re-occlusion?
- What determines the return of flow in the microcirculation? How can this be augmented?
- Can mechanisms of stroke recovery in the developing brain help to identify novel repair strategies in adults?
- How does microcirculatory reperfusion increase damage?
- Can answering these questions help us design therapies that may augment those that target large vessel occlusion?
- Develop combination and sequential therapies based on our understanding of known cell death mechanisms in ischemic neurons
and glia.
Despite substantial investigation into the biology of ischemic and hemorrhagic injury over the past two decades, there is still no effective therapy that targets the toxic events that develop within cells and tissues as a consequence of stroke. This type of therapy would fulfill an important need since some patients cannot be treated with clot-lysing compounds, and others could benefit from a strategy that combines neuroprotectants with clot lysis and other strategies to reduce tissue injury.
Combination therapy has been successful in treating other diseases, such as hypertension and diabetes, that have been resistant to treatments that target a single cellular or molecular mechanism. Emphasis should be given to research that promotes a more complete understanding of the natural neural pathways that protect the brain and of the blockade of pathways triggered after stroke that cause cell ddeath alone and in combination. Therapeutic strategies based on these mechanisms should be developed, particularly after validating them by in vivo or in vitro studies in human or primate tissues or cells. As an important practical issue, drug treatment could be improved greatly if we had a better understanding of the complexity of drug delivery to the ischemic brain and optimized transport of drugs into injured tissue. This information is essential to interpret complex outcomes from clinical trials and to improve the possibility of identifying more effective treatments.
To develop combination therapy with a high probability of efficacy in humans, members of the SPRG emphasized the need to develop and validate large and small animal models that reflect the complexity and diversity of the human brain and its responses during stroke. To facilitate model development and validation, the genome of large animals (e.g., pigs, sheep, and primates) should be sequenced along with the use of mathematical and statistical methods to improve the efficiency of combination drug therapy. Molecular imaging technologies should also be developed to profile gene expression after stroke, to validate stroke in animal models, and to identify therapeutic targets. Ideally, these technologies will inform us about the molecular, cellular, and synaptic events that predict stroke outcome, response to therapy, and recovery of function in humans.
- Characterize the mechanisms and time course of remodeling and recovery after stroke, at both the systems and cellular levels.
The SPRG members strongly emphasized the need to develop new therapeutic approaches to restore lost motor and cognitive function after stroke. At the moment, very little is known about the mechanisms that govern stroke recovery, and the natural history of recovery in humans and in animal models is incompletely understood. Evidence from brain injury in the clinic, particularly in children, strongly suggests that the brain does exhibit self-repair mechanisms that involve complex coordination between endogenous and exogenous elements, including blood vessels of the brain, neurons, and glial cells. However, the precise molecular and cellular events are not well understood. Nevertheless, it is becoming increasingly clear that brain recovery and remodeling occurs in response to external influences such as drugs and physical rehabilitation. To understand and perhaps amplify this process, we need to characterize the molecular and cellular mechanisms by which behavioral experience and environmental enrichment modulate the recovery process in brain after stroke. In particular, we need to develop rational pharmacological strategies based on these molecular mechanisms and determine the importance of genetic factors as a predictor of stroke outcome. Finally, we need to explore the potential use of stem cell technology as a tool to augment brain recovery in adult and pediatric stroke patients.
RESOURCE PRIORITIES
There is general agreement that the development of new and emerging technologies, as well as the application of existing ones, will be necessary to implement the research and scientific priorities and goals discussed above.
There is also general agreement that, more specifically, the seven resource priorities listed below, identified in many of the breakout sessions, will be necessary to meet those goals. These resources will help researchers generate and test hypotheses important to understanding all basic and clinical aspects of stroke, and to advance the prevention, diagnosis, prognosis, treatment, and rehabilitation of stroke patients. All of these priorities were considered equally important in accomplishing the overall goals of the PRG.
RESOURCE PRIORITIES- Emerging Array Technologies
- Translational Models
- Imaging Technologies
- Clinical Trial Technology
- Stroke Centers Network
- National Databases
- Education And Training
- Develop and apply emerging array technologies that have an impact on stroke.
Breakthroughs in science and technology have altered immeasurably the practice of neurology and have improved our understanding of basic disease mechanisms. Gene microarrays, in particular, are a recent breakthrough developed from advances in miniaturization, microfabrication, and high-density chip technologies that provide state-of-the-art platforms for genomics, proteomics, and pharmacogenetics. Microsystems such as these may become useful to generate data reflecting changes in enzyme activity, protein-protein interactions, and receptor-ligand binding plus gene expression. In addition, chip technologies may one day provide an individualized molecular portrait of stroke and its recovery course as well as a blueprint for therapy. Nominating and then testing candidate genes or mechanisms of interest individually will no longer be required, as thousands of different gene candidates can be assessed simultaneously within a single drop of fluid. Used in conjunction with molecular imaging techniques, markers in blood or other body fluids may then be used to profile stroke as it evolves. By applying these techniques, we may learn how molecules compromise cells, as well as parse their individual contributions to stroke pathogenesis.
Whereas gene chips and arrays use micron-based technologies, nanotechnologies focus on even more miniaturized systems and the manipulation, assembly, and targeted delivery of molecules into nanoparticles for applications such as biosensing, drug delivery, and cell repair. At such dimensions, nanoparticles may be particularly useful because the blood-brain barrier becomes less of an obstacle to drug delivery during stroke.
High-throughput initiatives, albeit exciting, are expensive and require centralized resources and high-throughput data analysis (bio-informatics). The sheer weight of the information generated, which is often non-intuitive and cryptic, can be daunting, and will require advanced data processing capabilities. The SPRG embraces the notion that emerging micro- and nanotechnologies will make it possible to investigate stroke in ways not previously possible.
- Develop and validate large and small animal models that reflect the complexity and diversity of the human brain and its responses
during stroke.
One theme raised in many breakout sessions was the need to reconcile clinical and laboratory disciplines in all areas of stroke research. This includes better models of stroke disease, especially in primates.
Improved animal models are needed to accomplish all five of the SPRG research and scientific priorities; their availability would help to advance drug development as well as our understanding of basic stroke biology. In this task, special emphasis needs to be given to species differences in hemostasis, inflammation, white matter content, and brain size, as well as vascular considerations such as ana-tomical distribution and regulation. Model validation is deemed essential and will require, at a minimum, the use of microarray and imaging tools and the development of physiologically based behavioral and pharmacological assays that accurately reflect the human condition in both short- and long-term studies.
Potential applications include:
- Use of these models with high-throughput screening strategies (see above) to identify pre- and post-stroke peripheral markers that are predictive of stroke risk, impending stroke, recovery, and outcome.
- Use of these models and molecular imaging tools to inform us about tissue and cellular responses, within both brain and cerebral blood vessels, that render tissue vulnerable to blood flow compromise. In addition, these models should be used to define the molecular correlates of the therapeutic window during reperfusion.
- Use of animal models to facilitate laboratory and imaging studies of macro- and microcirculatory pathology, hemostasis, and reperfusion in a cerebrovascular bed more closely simulating human stroke.
- Use of animal models to enable investigators to better evaluate the pharmacodynamics of therapies targeting the pathophysiological cascades in neurons and glia after ischemia and hemorrhage.
- Use of animal models for preclinical screening of leading drug candidates and for evaluating pharmacokinetics of the different agents used in combination therapy.
- Use of genetic engineering tools in animal models to examine the impact of specific genes on cerebral vessels and their interaction with tissue matrix, white matter, glial cells, and neurons in small and large animals (e.g., primates).
- Use of models to better understand hemostasis and platelet function and their perturbations before, during, and after stroke treatment with antithrombotic drugs.
- Use of animal models for developing and testing biomedical engineering devices that augment reperfusion or novel delivery systems of therapeutic drugs.
Models can also be useful in the context of developing a more comprehensive understanding of stroke recovery and developing treatments that enhance stroke rehabilitation and maximize the potential for restoration of function. Accordingly, these models can be used to:
- Study the genomic and proteomic correlates of brain plasticity during recovery of function after stroke.
- Allow behavioral and functional imaging studies of the brain during recovery and determine how they are affected by environmental, biological, and pharmacological interventions.
Because animal models for stroke are technically difficult to develop and often require special facilities for surgery, imaging, and housing (e.g., primates), we need to encourage collaborations between groups dedicated to perfecting these models and laboratories applying these models to complementary research interests. Development of models of both brain ischemia and hemorrhage remains a high priority.
- Expand brain imaging capabilities.
Brain imaging already has revolutionized the diagnosis and management of stroke. We need to develop new imaging techniques. We also need to better understand the existing modalities, to improve our understanding of stroke pathophysiology and recovery, and to provide a trans-lational link between experimental advances and clinical applications.
Imaging techniques could be used to:
- Identify neuroimaging markers of "tissue at risk" in order to better link therapy to tissue pathobiology.
- Understand the effects of reperfusing the brain on the underlying vascular pathology, cerebral blood flow, and blood-brain barrier integrity.
- Improve clinical trial design in both patient selection and in assessing drug activity within the brain.
- Improve continuous non-invasive monitoring of patients at the bedside, to better evaluate the evolution of injury, evaluate treatment, and assess risks.
- Inform about the status of the blood-brain barrier.
- Optimize drug delivery by establishing parameters for dose, duration, and time window.
- Provide predictive information about outcomes in both acute and chronic stroke.
- Allow improved mapping of brain plasticity and reorganization.
In addition to the above, there are important unmet needs that require further technology development and validation. The needed technologies include:
- Imaging methods that directly reflect electrophysiological and synaptic activity, rather than blood flow. Such techniques can be used to assess neuronal networks and other neural substrates responsible for good recovery following stroke.
- Cellular- and molecular-based imaging techniques. These can provide new opportunities to characterize and classify stroke in ways not previously possible (e.g., the choice of acute treatments targeted to specific cellular and molecular events during stroke).
Thus, the SPRG places a high priority on developing and validating new imaging markers and techniques to facilitate the spatio-temporal assessment of stroke at both the tissue and the molecular level.
- Improve clinical trial technology.
Clinical trials are necessary to define how to best apply basic research advances to the treatment of patients. Building on the conspicuous successes of NINDS-sponsored clinical trials in stroke prevention and treatment during the past decade, new, better designed clinical trials will use innovative approaches to get needed answers efficiently and expeditiously.
Clinical trials in stroke are time consuming and expensive. These constraints may serve to discourage innovative or start-up strategies as well as drain the good will and resources of funding agencies, investigators, clinical resources, and patients.
We need to develop more streamlined clinical trials of prevention strategies and acute stroke therapy by improving trial design, developing and testing new outcome measures, and forming clinical trial consortia/networks. Depending on the questions asked and the population studied, both large simple trials and smaller focused trials with surrogate endpoints should be explored. Proper guidelines for such studies should be developed. We need to develop outcome measures with more relevance to the patient as well as measures that might be more sensitive to therapeutic effect than those currently used. Treatment trials in certain clinical areas have been relatively ignored and need more attention; these include intracerebral hemorrhage, pediatric stroke, and rehabilitation.
There also needs to be greater collaboration between industry and academia in designing, prioritizing, and funding clinical trials. Networks of collaborating centers and individuals interested in conducting clinical trials should be established to help prioritize resources and expedite trial execution. The establishment of specialized centers pioneering translational research in acute stroke will expand treatment options for acute stroke when prevention fails. Finally, we need to develop better methods for encouraging more physicians, patients, and advocacy organizations to participate in clinical trials. Clinical trials are the front lines in the fight against stroke and will define the next generation of treatments used in clinics throughout the world.
- Develop stroke center networks.
The SPRG recognizes that existing and future preventive and acute interventional therapies need to be more widely and rapidly adopted by health care workers and patients. This could be accomplished by a better understanding of the existing barriers to health services implementation pertaining to stroke, including the lack of incentives, information, and essential personnel and technologies. We need more accurate and universal information regarding existing practice patterns and we need to understand the administrative barriers to obtaining medical resources and care.
To promote better implementation we need to develop and test interventions aimed at improving community practice, and partner with payors and other groups in stimulating good practice. We need greater regional collaboration to develop multidisciplinary teams (i.e., stroke center networks) that can better overcome the local barriers that exist to implementing stroke prevention and therapy, including health disparities.
- Improve databases for stroke.
A national stroke surveillance system would establish a database of stroke that would help characterize the public health burden of stroke and identify those populations that need special emphasis. An effective database would include substantial socioeconomic and ethnicity detail that is often unavailable when doing epidemiologic analyses. A data-base would also facilitate the study of the many stroke-related conditions that occur too sporadically for randomized comparison studies.
Such a database will also facilitate the application of targeted genetic analyses. The complex variability of the stroke phenotype requires such a database in order to carry out research on stroke genetics. Genetic databases are also needed. These would be particularly important in sharing and sifting through the exploding information in this area. A centralized genomic/proteomic/ bioinformatic facility would support the establishment of such a database.
Stroke information that is widely available to clinicians in an electronic format would help to foster the development of collaborative consortia and standardized methodology for conducting research and for patient management, and might help increase implementation of therapies.
- Expand education and training.
It is clear that prevention, diagnosis, and treatment of stroke is a public health problem that is too large to be managed only by stroke specialists. Yet training of other medical personnel in modern stroke management is currently inadequate. Non-neurologists and neurologists alike need more exposure to the advances made in the field of stroke. Even more important, the next generation of medical personnel should receive an educational curriculum, starting early in professional school, that ensures they will be more knowledgeable about stroke.
We also need to improve the training of neurologists in the emerging disciplines that will be critical for researching and applying new stroke therapies, including genomics, endovascular therapy, imaging, and rehabilitation. Existing barriers to such cross-training should be identified and eliminated.
As we focus our research on the interface between circulation and the brain, the lack of neuropathological information about and expertise needed to effectively study stroke is recognized as a major deficiency.
CONCLUSION
Stroke is the third leading cause of death and a major disabler of the American people. Although many challenges lie ahead, we are currently experiencing an extraordinary and unprecedented time of scientific growth and technological breakthroughs. Our greatest advances in stroke research have been made in the prevention of stroke through surgical and drug therapies. Early stroke treatment with t-PA (tissue plasminogen activator) has reinforced the belief that stroke is a treatable disease. However, now we are in great need of new treatments that reduce damage and promote recovery once a stroke has occurred. To attain these reachable goals, we will require new initiatives and new applications of technologies that can advance the field of stroke in the laboratory and at the bedside.
The research and scientific priorities and resource priorities identified by the SPRG provide an outline for academia, industry, government, and patient advocates to guide progress in stroke research. Commitment and joint sponsorship among these vested communities to address these priorities will facilitate the development of creative solutions to prevent, diagnose, and treat stroke in the current decade and beyond.
TopScientific Session Reports:
Full Reports of the Stroke Progress Review Group
Roundtable Meeting Breakout Sessions
Cerebrovascular Biology
Co-Chairs: Bruce M. Coull, M.D., and Donald Heistad, M.D.
Participants:
Richard A. Cohen
Frank M. Faraci
Mary Gerritsen
Gary Gibbons
Willa A. Hsueh
J. Paul Muizelaar
Stephen M. Schwartz
Katherine Woodbury-Harris
Research on basic vascular biology has now provided us with the underpinnings needed to understand vascular diseases in specific organs. This critical information includes an understanding of how vessels develop, as well as the molecular and functional differences between the endothelial and smooth muscle cells making up arteries, veins, and capillaries.
It is likely that extension of this basic biology to the neurovasculature will lead to fundamental new directions in cerebral vascular biology (as it already has in the biology and pathology of other organ systems). Major advances in the understanding of causes and treatment of stroke (especially cerebral hemorrhage) are likely to be delayed until this improved understanding of neurovascular biology is achieved. As a precedent, lessons learned from vascular biology were critical for recent advances in treatment of myocardial infarction.
Obvious areas of interest include characterization of physiological responses to acute stimuli and to major risk factors, especially hypertension and diabetes, as well as inflammatory diseases involving the nervous system. The availability of comprehensive human and mouse genetic data, as well as newly developed technologies including arrays, genetically altered mice, and proteomics, should move the field of cerebrovascular biology very rapidly.
CHALLENGES AND QUESTIONSThe neurovasculature has many properties that are not found in other organ systems. These properties likely account for a great deal of neurovascular pathology, including not only obvious targets such as neurovascular spasm and stroke, but also less obvious targets as diverse as brain metastases, develop-mental anomalies, and inflammatory diseases.
We already know that brain endothelium is distinctive, as manifested by the blood-brain barrier, for example. The role of smooth muscle cells in the distinctive characteristics of cerebral vessels is not well understood, and the likely role of smooth muscle in determining the unique phenotype of cerebral endothelium has not been explored. Adventitia, which has emerged as an important tissue in regulation of blood vessels, is less prominent in cerebral vessels than in extracranial vessels. The functional implications of this structural difference are not clear.
A number of opportunities for study already exist based on current knowledge of vascular biology. For example, although we have some knowledge of the effects of risk factors on cerebral blood vessels, other important risk factors (including atherosclerosis, diabetes, smoking, and aging) have received little attention. Newly recognized risk factors, including hyperhomocystinemia and chronic inflammation, may be fertile areas for study.
Although inflammation and infection may play an important role in cerebral vascular disease, new classes of anti-inflammatories directed at vascular adhesion molecules, chemotactic factors, and the death receptor family have received little attention in the neurovascular system.
The role of oxidative and antioxidant mechanisms in cerebral vessels is an especially promising area of research. Recent studies suggest that oxidant injury may be an underlying mechanism in vascular injury in response to a variety of stimuli.
BARRIERS
- It is likely that the relatively small size of intracranial vessels and the difficulty of anatomical access to them have led most vascular biologists to focus on the aorta and peripheral blood vessels, rather than the cerebrovasculature.
- Basic research of neurologists, neurobiologists, and neurosurgeons usually focuses primarily on neurons and glia rather than blood vessels. Consequently, research in cerebral vascular biology lags behind that in other organs, and representation on grant review committees in NINDS is limited.
- There may be some reluctance to apply basic approaches of vascular biology to neurovascular vessels, to avoid simple replication of findings. Yet there are many fundamental differences from extracranial vessels that make studies of intracranial vessels of great interest.
Current and future research should focus on building the basic knowledge of vascular biology needed to proceed with more broadly based efforts with a disease focus. The obvious challenge is to leverage current knowledge of vascular biology with the opportunities offered by new methods to accelerate research. Applications of arrays, genetically altered mice, and proteomics, combined with our existing, finite knowledge of the entire set of transcribed genes, should greatly accelerate research in this area.
- One approach to expanding our knowledge is from vascular development. Today, at a systemic level and in certain specific tissues, we know a great deal about growth factors and receptors involved in the primary differentiation of endo-thelium, the role of endothelium in recruiting smooth muscle, and the role of smooth muscle in determining endothelial behavior. Developmental biology of cerebral vasculature, however, has received little attention.
- We know enough about fruitful approaches from the peripheral vasculature to suggest areas of focus in the brain and vasculature. For example, it is very likely that specific vasculatures have very specific sets of genes that control cell function. These sets of genes might be called "molecular phenotypes," and are obvious targets for analysis by new methods of transcription and proteomic systematic analysis. It would be of great value to know the extent of endothelial and smooth muscle phenotypic specificity in different cerebrovascular beds, as well as the modulation of these phenotypes in the face of risk factors known to affect cerebrovascular disease.
- Another useful tool comes from murine genetics. Genetically altered mice have altered functions in areas ranging from the formation of the layers of the vessel wall to inflammation and angiogenesis. These mice can be used to address critical questions in neurovascular biology by combining the mouse models with advanced physiological methods for determining murine neurovascular function. Processes of specific interest may include the relative roles of growth and proliferation versus cell death as determinants of vascular responses to several stimuli.
Priority 1:
Understand developmental and basic aspects of cerebral vascular biology.
The basic discoveries of developmental vascular biology have identified mechanisms underlying not only the formation of blood vessels, but also the mechanisms of vascular response to injury in general. Brain-specific vascular biology is needed to identify the precise mechanisms underlying neurovascular disease. Specific questions to address include:
- Embryonic origins and development of neurovascular endothelium and smooth muscle.
- Phenotypic differences between the endothelium, smooth muscle cells, and adventitia of the neurovasculature, as compared to other vasculatures, using arrays and other contemporary systematic analysis.
- Development of suitable in vitro and transgenic models to understand the interactions of endothelium and smooth muscle with glia and neurons.
- The unique properties of the cerebro-vascular endothelium, including the BBB, transport properties, cell trafficking, and metabolism, applying findings from the genome project and the systematic tools of molecular biology.
Priority 2:
Understand mechanisms of response to injury.
Reactive oxygen species are products of metabolism in ischemia, and are produced by specific enzymes. Oxidative mechanisms may regulate vasomotor responses of cerebral vessels to ischemia, the inflammation accompanying brain ischemia, remodeling associated with cerebral vasospasm, and chronic effects of risk factors on cerebral vascular structure and function. Specific areas to be explored include:
- Genetic regulation of responses to injury.
- Regulation of cerebral vascular growth and apoptosis by oxidant or other mechanisms.
- Adherence and expression of adhesion molecules.
- How mechanisms associated with risk factors affect cerebral blood vessels.
- Clotting and anticoagulant mechanisms in neurovascular vs. peripheral blood vessels.
- Angiogenesis, in relation to injury and to age (with implications for germinal matrix hemorrhage).
- Inflammatory responses and mechanisms.
- The molecular changes in vasculature underlying hemorrhage in premature infants, neonates, and adults.
Priority 3:
The application of developmental and basic aspects of cerebral vascular biology and mechanisms of response to injury can provide a deeper understanding of vascular patho-physiology of great importance to stroke. The approaches outlined above can address the consequent effects of recognized risk factors for stroke and may help to elucidate new stroke risk factors. Research priorities include:
- Animal models.
- Development and/or refinement of animal models that reflect patho-physiologies of cerebrovascular risk factors such as atherosclerosis, diabetes mellitus, hypertension, and intracerebral hemorrhage.
- Development of models that accurately reflect and allow us to understand germinal matrix hemorrhage, berry aneurysm, and perinatal stroke.
- Cerebrovascular neuropathy.
- Application of advanced molecular biological approaches.
- Integration of molecular and functional studies with neuroimaging techniques.
- Studies to distinguish large-vessel pathophysiology from microvascular pathophysiology.
- Determinants of cerebral vascular aging.
- Identification of preclinical markers.
large number of resources now exist that may enhance the study of the neuro-vasculature, but they have not been fully evaluated. Resources that should be evaluated include:
- Genetically modified mouse models targeted to specific problems of vascular biology, including selected expression systems and genes known to be critical to the formation and pathology of blood vessels. For example, there are numerous murine models of atherosclerosis, but the neurovascular physiology and pathophysiology of these animals has not been evaluated.
- A stroke-prone mouse.
- Animal genetics, including congenic animals generated to target heritable diseases of the vasculature, such