Disorders A - Z:   A    B   C    D    E    F    G    H    I    J    K    L    M    N    O    P    Q    R    S    T    U    V    W    X    Y    Z

Skip secondary menu

Final Report of the Stroke Progress Review Group – January 2012


Additional information about Stroke PRG 

Introduction

In 2011, the NINDS asked the Stroke Progress Review Group (SPRG) to conduct a final review of the stroke research landscape, ten years after the first SPRG established research priorities for the field (SPRG 2002 Report). The final review was overseen by NINDS staff members and the SPRG co-chairs Drs. Michael Moskowitz and James Grotta. Each working group consisted of two co-chairs, one liaison co-chair, 8-10 working group participants as well as 1-3 NINDS liaisons. Each group worked together via conference call and web-based collaboration to evaluate progress made over the last five years and identify new or unmet challenges, as well as the most promising future directions for each topic area. This comprehensive assessment is the first step of a 2-phase stroke planning process that NINDS undertook in 2011-2012.  During the second phase, NINDS brought together stroke experts and the broader community to build upon the SPRG’s final review and come up with the highest priorities for stroke prevention, treatment and recovery research. The results from the overall stroke planning process are now available. (click here for the report from the Stroke Research Priorities Meeting).

Topic area working group summaries and top priorities

Topic area working group full reports

SPRG Final Review participants


Topic area working group summaries and top priorities

ACUTE ISCHEMIC STROKE TREATMENT (View the Full Report)

Co-Chairs: Jeffrey Saver, Helmi Lutsep, Patrick Lyden 

Members: William Barsan, Kyra Becker, Gabrielle DeVeber, Jeff Frank, Kama Guluma, Clarke Haley, Michael Hill, Reza Jahan, Pooja Khatri, Tom Kwiatkowski, Brett Meyer, Raul Nogueira, Larry Weshsler

NINDS Liaison: Scott Janis

STROKE PRG 2011 REVIEW REPORT SUMMARY

Progress has been made on the 2002 and 2006 SPRG goal to develop therapeutic agents that open blood vessels in more patients and do so more frequently, faster, and with greater safety, but further progress is a high priority. We also recommend prioritization of studies that will potentially increase eligibility for IV rtPA.

The 2002 Stroke PRG correctly foresaw that neuroprotective therapy started late with agents targeting single mechanisms was unlikely to be successful in humans. The Stroke PRG helped foster novel strategies, including developing single agents with pleiotropic, robust effects, like hypothermia and albumin, and prehospital techniques for hyperacute initiation of treatment within the first minutes after onset.

Since the 2006 report of the SPRG, there has been a significant increase in the number of certified stroke centers and attention to systems of care with an associated improvement in delivery of stroke therapies and improvement in outcomes. Continued expansion and integration of care across the spectrum of acute treatment facilities is needed to ensure access to acute stroke treatment for all Americans.

The field of pediatric stroke has developed rapidly, and has reached the stage where focused funding prioritization is required to make further advances including understanding mechanisms and optimal treatments. The existence of highly motivated and collaborative researchers in this field provides tremendous potential for leveraging research productivity.

In the past 10 years, there has been a substantial improvement in the integration of Emergency Medicine investigators in NINDS funded stroke research, most prominently in the successful research networks - NETT and SPOTRIAS. There has also been increased involvement of prehospital providers in emergency stroke research and a successfully recruiting phase 3 clinical trial in stroke which enrolls in the prehospital setting.

Since the 2006 Stroke PRG report, much progress has been made in telestroke: more telestroke programs are in place, rt-PA rates have increased, and clinical trials showed excellent decision-making efficacy using telestroke. With continued support from NINDS, clinicians and researchers can expand current telestroke procedures, leverage telemedicine for research recruitment, and innovate on smartphone and other emerging platforms.

Recent changes in hospital reimbursement improved the climate for development of stroke centers, but also created new challenges: a disincentive to transfers of “drip and ship” patients in a stroke system of care and a barrier to recruitment of patients into acute stroke clinical trials. Further research regarding the impact of these issues on the public health problem of delivering acute stroke services is urgently needed.

The SPRG process furthered awareness of potential sex differences in acute stroke trials. However, future clinical trials need to include sufficient numbers of women and under-represented race-ethnic groups to evaluate treatment effects in these populations.

In acute ischemic stroke therapy, the mechanism of stroke is less important than the location of the occluded artery. Thrombus pathology would be useful if it could then be shown to help stratify therapeutic decision-making. Assessment of interventions to prevent early recurrent stroke or to prevent progression of existing deficits is needed during the acute hospital stay. Further assessment of brain, vascular, and cardiac imaging technologies, their diagnostic utility and the timing of their use, is needed.

Top priorities for future directions:

1. Make reperfusion therapy swifter, safer, and surer: Early recanalization currently is, and likely always will be, the most effective therapy for acute ischemic stroke. Present recanalization treatments are limited by infrequent achievement of complete reperfusion, long delays to reperfusion, and high rates of hemorrhagic complication. New drugs and devices, alone and in combination, are needed to enable cerebral reperfusion interventions to achieve rapid, complete and sustained vessel patency in all patients harboring salvageable tissue, with no risk of hemorrhagic transformation.

2. Continue to study cerebral cytoprotection early and after reperfusion with potent, pleiotropic interventions, and with optimal management of physiologic parameters: Cytoprotective therapies continue to hold promise as adjunctive treatment to reperfusion, and the most promising avenues for deriving benefit include initiation in the hyperacute 0-2 hour period to stabilize the penumbra until reperfusion, use of agents blocking reperfusion injury in the post-recanalization period, and study of single and combination agents that have demonstrated extreme potency and polymorphic effects in interrupting injury pathways. In addition, developing firm evidence for optimal protocols to manage blood pressure, glucose, oxygen, and other physiologic parameters would provide improved cytoprotective care to all acute stroke patients.

3. Refine and leverage effective acute stroke clinical trial networks: In the last decade, NINDS and other agencies successfully launched cooperative study groups to conduct acute stroke trials, including SPOTRIAS (NINDS, phase 2), NETT (NINDS, phase 3), and IPSS (pediatric). This established clinical trial infrastructure is poised to drive rapid, iterative advance in acute stroke care. NINDS should prioritize a review of these networks and then refine and optimize them based on both internal experience and experience in kindred disease states; such network reviews should drive to make translational treatment trials inexpensive, efficient, and successful.

Top

BIOLOGY OF REPAIR (View the Full Report)

Co-Chairs: Michael Chopp, S. Thomas Carmichael, Jack Parent

Members: Steven Cramer, Theresa Jones, Randolph Nudo, Sean Savitz, Gary Steinberg, Raghu Vemuganti, Zheng Gang Zang

NINDS Liaisons: Francesca Bosetti, Tim LaVaute

STROKE PRG 2011 REVIEW REPORT SUMMARY

New Stroke research opportunities, emerging topics, and unresolved areas since 2007

miRNA: miRNAs likely play important roles in mediating neurological recovery and inducing restorative processes.

Epigenetics: Investigate the role of epigenetic phenomenon that include DNA methylation, acetylation and histone functions after stroke.

Endogenous neurogenesis: The role of adult-generated neurons in repair after stroke remains unclear. 

Cell transplantation: The biological mechanisms through which cell transplants act to promote repair should remain a scientific focus in order to optimize such therapies.

Coordination of vascular and neural circuit remodeling: A better understanding of spontaneous vascular structural remodeling process after stroke, the interdependence of activity-dependent circuitry remodeling, new vessel formation and vessel stabilization, and sources of variability in these responses (e.g., with age) are important for optimizing and timing restorative treatment strategies. 

Diabetes and aging: Both the diabetic and aging brain may have a distinctive biology from the young brain and in recovery, but this area has not been investigated in detail.

Imaging recovery: There is a need to improve the MRI capabilities and other imaging modalities to non-invasively monitor brain recovery. Translation of results to humans is paramount, underscoring the value of imaging methods to provide direct comparisons between rodent and human brains.

Multiphoton and other live imaging approaches: Linking repair processes to behavioral function requires sophistication in behavioral as well as imaging approaches.

White matter injury and repair: The cellular mechanisms of white matter repair have not been identified.

Stroke repair biomarkers: Biomarkers for neural repair are needed for mechanistic studies and clinical trials.

Developing and diversifying stroke animal models: There is a major need to both better encompass the diversity of human stroke in animal models.

Electrical and magnetic stimulation: TMS and tDCS require a rigorous understanding of underlying neurobiological principles in order to be fully utilized in clinical populations.

Brain machine interfaces: Studies that focus on developing an understanding of the neurobiological effects of such artificial communication bridges are needed to advance this technology to stroke and other neurological conditions.

Top priorities for future directions:

1. Identify critical stroke repair/restorative mechanisms at the molecular, cellular, tissue and systemic levels:

a) Identify axonal and dendritic sprouting, neurogenesis, angiogenesis, epigenetic and small RNA alterations, remyelination and white matter repair, glial activation, altered network activity, contralateral plasticity

b) Identify biomarkers to monitor effects of manipulations on recovery (e.g., imaging neural plasticity and repair, neuroplasticity and repair)

2. Define and optimize restorative therapies, including cell-based, pharmacological, brain-machine interface, and brain stimulation approaches, based on mechanistic advances

a) For cell therapies, investigate and identify cell types, physical properties of grafted cells and associated material/scaffolds, optimal -non-invasive monitoring of graft or endogenous response

b) For all restorative therapies, investigate and identify therapeutic windows and timing of restorative intervention

3. Translate cell-based, pharmacological, brain stimulation and behavioral manipulations with associated biomarkers and neuroimaging from animal models to clinical trials.

a) Identify animal stroke models particularly useful for studying neural repair, specifically investigate animals models associated with elevated stroke risk and morbidity/ mortality, including ageing, diabetes and hypertension

b) Optimize behavioral and cognitive outcome indices of recovery

c) Identify optimal therapeutic window for intervention

d) Support preclinical safety and efficacy data gathering

Top

CEREBROVASCULAR BIOLOGY AND NEUROVASCULAR UNIT (View the Full Report)

Co-Chairs: Costantino Iadecola, Marilyn Cipolla, Frank Faraci

Members: Nabil Alkayed, Robert Bryan, Turgay Dalkara, Donna Ferriero, Edith Hamel, Zvonimir Katusic, Raymond Koehler, Charles Leffler, Chris Schaffer, Danica Stanimirovic

NINDS Liaisons: Thomas Jacobs, Erik Runko

STROKE PRG 2011 REVIEW REPORT SUMMARY

The endothelium has emerged as a key player not only in the regulation of vascular tone, but also in maintaining the structural and functional integrity of the neurovascular unit (NVU). As a major site of end-organ damage in cerebrovascular disease, it represents a key target for prevention, as well as therapy and recovery of function. Understanding the molecular bases of the interaction between endothelial cells and other cells within the vessel wall and NVU may harness the broad protective potential of the endothelium.

Progress has been made in understanding the structure and function of vascular smooth muscle (VSM) and pericytes, but fundamental questions concerning their normal and pathophysiological roles remain. For example, the mechanistic bases of autoregulation and the role of newly discovered ion channels remain elusive. Excitation-transcription coupling in VSM and pericytes and their interaction with neurons and astrocytes needs to be better understood. New technologies to investigate large and small vessel function in health and disease will advance this area further.

Advances in neurovascular and gliovascular signaling in health and disease have occurred as a result of more precise structural and functional in vivo imaging of neurons, astrocytes and cerebral vessels. These newer technologies need to be applied to unravel the mechanisms of neurovascular dysfunction in cerebrovascular pathologies. Protecting the NVU as a whole may limit brain damage and enhance repair in stroke, as well as in Alzheimer’s dementia and other neurodegenerative conditions.

Progress has been made in understanding blood-brain barrier (BBB) formation and maintenance, transporters and ion channels, but the mechanisms of BBB disruption by risk factors and cerebrovascular diseases remains understudied. Knowledge gaps include a lack of detailed understanding of molecular and functional changes in BBB in disease, and strategies to protect and repair the BBB. Novel approaches for drug delivery across the BBB, as well as BBB models that better mimic the in vivo situation, should promote new treatments for stroke and other neurological diseases.

A greater level of complexity has emerged in the vascular damage caused by stroke risk factors and cerebrovascular diseases, centered on the interactive role played by immunity, inflammation, and oxidative stress. New efforts need to define cell-specific pathways and molecular mechanisms of disease, as well as the pathogenic interactions between cell types in large and small vessels. Models that take into account risk factors, gender and age, as well as new genetic, molecular and imaging tools are needed.

Challenges remain in understanding sex-specific mechanisms, course, and response to therapy of cerebrovascular disease at all ages. Knowledge is still lacking in understanding the cerebrovascular correlates of the menopausal transition and the impact of hormone replacement therapy. Clinical studies on the predisposition to preeclampsia with a focus on cerebrovascular disease and stroke risk factors should be conducted in parallel with the development of relevant animal models.

Understanding normal cerebrovascular regulation and the pathological alterations induced by asphyxia/ischemia in the developing brain is critically important for prevention, diagnosis, and treatment in fetal, neonatal, and childhood hypoxic-ischemic events. More knowledge is needed on the pathological events triggered by asphyxia-ischemia and stroke in newborns and children, and how the causes, effects, and healing processes may differ from the adult. In pediatric stroke, efforts should be directed at developing pre-clinical models so that mechanisms and risk factors can be studied more appropriately.

Top priorities for future directions:

1. Elucidate the genomic, proteomic features and the corresponding functional correlates of vascular and perivascular cells, and cells of the NVU. Priorities include: (a) defining cell-specific and molecular mechanisms of disease for all segments of the brain circulation, from large cerebral vessels outside the brain to intraparenchymal vessels in intimate contact with neurons and astrocytes; (b) elucidating the changes that occur during development and aging, and investigating their sex specificity and the modifications induced by functional activation in the normal state, after injury and during repair processes.

2. Elucidate the signaling mechanisms governing the functional and trophic interactions among the cellular elements of the vasculature, as well as their relationships to neurons and perivascular cells in the developing, adult and aging brain, and in both sexes. Assess how activation, stroke risk factors and injury alter such interactions, and how damage to one cell type alters the homeostasis of the vessel wall, including function of the NVU and the BBB.

3. Promote novel applications of current technologies, as well as development of new molecular, cellular, and imaging tools to dissect the inner workings of vascular cells and their interactions with neurons, astrocytes and perivascular cells. Translation of newly identified mechanisms and pathways into therapies will require well controlled disease models incorporating multiple stroke risk factors and taking into account age (neonatal, pediatric, adult, and old age) and sex. Efforts to develop a new generation of investigators in cerebrovascular and neurovascular biology will be vital to advance the field to the next level.

Top

CLINICAL TRIALS (View the Full Report)

Co-Chairs: Joseph Broderick, Thomas Brott, Karen Johnston

Members: Colin Derdeyn, Pam Duncan, Nicole Gonzales, Yuko Palesch, Rema Raman, Robert Silbergleit, Tanya Turan, Kenneth Cavanaugh (reviewer), Natalie Getzoff (reviewer)

NINDS Liaisons: Scott Janis, Claudia Moy, Salina Waddy

STROKE PRG 2011 REVIEW REPORT SUMMARY

Key concepts gleaned from recent trials that will drive future research.

1) The results of the COSS and SAMPMPRIS Trials suggest that future stroke prevention trials should probably include aggressive treatment of vascular risk factors in the protocol and open the question of whether the results of the asymptomatic endarterectomy trials performed over a decade ago are still valid in the modern era of statins and newer antihypertensive medications.

2) The past five years has also seen the development of several advances in stroke clinical trial methodology and infrastructure that can impact present and future trials.

3) The impact of CMS reimbursement policies on trial recruitment has become very apparent, with the success of SAMMPRIS and CREST and the struggles of IMS 3 and RESPECT.

Top priorities for future directions:

1. Improve efficiency of clinical trials:

a) Continued support/expansion of infrastructure and best recruitment practices to facilitate timely and efficient completion of trials (networks, NIH-sponsored national IRBs, resources for study monitoring)

b) Reimbursement for Phase IIb-III Trials by CMS/payors for promising but clinically unproven therapies prior to reimbursement for clinical delivery of technology of care, requiring coordination of federal agencies

c) Partnership with other countries to improve recruitment and generalizability

d) Minimization of overlapping and concurrent competing stroke trials

2. Improve trial design, conduct, and outcome assessment:

a) Centralized tools for trials for getting studies started and identification of well designed outcome variables that are consistent across studies

b) Training tools for new coordinators/investigators (building upon past successful trials)

c) Innovative statistical designs

3. Conduct clinical trials that advance current evidence-based therapies or for those conditions without a proven therapy:

a) Acute ischemic stroke trials that test treatments potentially more efficacious than IV tPA alone or use imaging to test treatments in imaging selected subgroups beyond 4 ½ hours

b) Acute intracerebral hemorrhage (medical and surgical)

c) Trials of patients with ruptured aneurysms

d) Trials of aggressive medical therapy vs. interventional treatment of asymptomatic carotid stenoses

e) Trials of new anti-thrombotic agents in patients without a cardioembolic source who fail aspirin

f) Trials of behavior change/primary stroke prevention (beyond scope of NINDS alone)

g) Phase I, II and III trials of neurorecovery therapies

Topic area working group full reports

Top

CNS HEMORRHAGE (View the Full Report)

Co-Chairs: Stephan Mayer, Neil Martin, Jaroslaw Aronowski

Members: E Sander Connolly, Nestor Gonzalez, Dan Hanley, J. Claude Hemphill, Richard Keep, Loch MacDonald, Adnan Qureshi, Lauren Sansing, Paul Vespa, Jeff Weitz, William Young

NINDS Liaisons: Tom Jacobs, Scott Janis

STROKE PRG 2011 REVIEW REPORT SUMMARY

Seminal Advances in CNS Hemorrhage Research 2007-2011

Reducing ICH growth. The FAST and INTERACT Trials confirmed that acute hemostatic and BP reduction therapy can reduce active bleeding and hematoma volume in ICH. Unfortunately, no clear and consistent benefit on outcome was demonstrated. Recent metanalyses have determined that a reduction in absolute ICH volume growth of 6 to 12 ml is required to improve outcome. These studies have set the stage for future studies combining these interventions within a very early time window.

Treatment of vasospasm. The CONSCIOUS 2 and 3 trials showed that clazosentan, an endothelin receptor antagonist, reduces angiographic vasospasm after SAH when given in combination with nimodipine. CONSCIOUS 3 showed benefit on its primary outcome, which incorporated death, infarction or deterioration from vasospasm, and rescue therapy. However, no clear benefit on outcome was realized. The sponsor of this industry-funded trial is considering a final phase III trial comparing clazosentan head-to-head against nimodipine.

Clot evacuation and tissue neuroprotection. STICH-2 is continuing to explore the role of open surgical evacuation for lobar ICH. Preclinical research and phase II clinical trials have demonstrated the feasibility of early clot evacuation (CLEAR, MISTIE, STICH) and novel tissue protection strategies (deferoxamine, pioglitazone) for ICH and IVH. These studies have set the stage for further phase III trials including possible combined treatment trials.

Important New Concepts and Opportunities in CNS Hemorrhage Research

Electrically-mediated brain injury. There is now recognition that cortical spreading depression (CSD) and related phenomena, such as spreading depolarization and ischemia, are frequent events when humans with SAH and ICH are studied with electrocorticography. These phenomena, in combination with non-convulsive EEG abnormalities, are a potentially important and treatable mediator of secondary brain injury that deserve further study.

Early brain injury in SAH. With improvements in aneurysm repair and treatment for vasospasm, there is emerging recognition that early brain injury resulting from the primary bleeding event is an important cause of SAH morbidity and mortality. There is a pressing need for further experimental and clinical research to elucidate these mechanisms of injury.

Novel outcome measures and assessment techniques. The failure of studies such as FAST and CONSCIOUS-2 to demonstrate clinical efficacy despite evidence of benefit using intermediate endpoints (such as hematoma growth and angiographic vasospasm) highlights the need for novel clinical trial designs with endpoints designed to optimally capture clinically meaningful treatment effects.

Top priorities for future directions:

1. Study blood and the neurovascular unit: Basic science research is needed to better understand the special nature of hemostasis and coagulation within the CNS and how it affects the neurovascular unit, with particular regard to electrical disturbances, cellular signaling, microvascular dysfunction, tissue inflammation, and matrix biology. There is still a need for more relevant models of acute hemorrhage-induced brain injury.

2. Conduct advanced imaging and physiologic studies in humans: Human data using time-based acute phase neuroimaging, multimodality physiological monitoring, tissue/molecular/biomarker analysis and genetic profiling is needed to better define the time window, mechanisms, and clinical impact of potentially-modifiable primary and secondary injury pathways during the acute phase of bleeding. Target pathways should be identified and validated in preclinical experimental studies.

3. Study surgical hematoma evacuation: Despite the negative results of the STICH trial, the proper role of surgical hematoma evacuation remains the most pressing unresolved clinical question in ICH management. More research is needed to better define the role of very early surgical intervention, and to develop novel image-guided minimally-invasive surgical interventions for deep hematoma aspiration. The phase II MISTIE trial and STICH-2 trials will prove useful in starting these efforts, but more work is needed.

Top

COAGULATION, HEMOSTASIS, AND ENDOTHELIAL CELL INTERACTION (View the Full Report)

Co-Chairs: Gregory del Zoppo, Maiken Nedergaard, David Pinsky, Jeffrey Weitz

Members: Ulrich Dirnagl, Paula Dore-Duffy, Peter Gross, Antoine Hakim, John Hallenbeck, Richard Keep, James Morrissey, Bruce Ransom, Marc Simard, Lydia Sorokin

NINDS Liaison: Thomas Jacobs

Exciting progress has been made over the last decade in our understanding of the complex events that accompany focal ischemia and hemorrhage; however, numerous problems remain that have yet to be solved.

STROKE PRG 2011 REVIEW REPORT SUMMARY

Broad Conceptual Advances

  • Characteristics of the neurovascular unit and its relevance to focal ischemia and hemorrhage
  • Relationship of the neurovascular unit to hemostasis
  • Innate inflammation

Unresolved Scientific Questions: The neurovascular unit and hemostasis

  • Integrity of the blood-brain barrier
  • Interaction of cellular and structural components of the neurovascular unit
  • Vascular hemostasis in the central nervous system (CNS)
  • Neuron-vascular relations
  • Innate inflammation

Resources Required for Resolving Outstanding Questions: The neurovascular unit and hemostasis

  • Need for appropriate models for the neurovascular unit and CNS hemostasis
  • Understanding of the components of the neurovascular unit
  • Translational models
  • Introduction of evaluation of comorbidities to problems of neurovascular unit

New Key Research Areas that have Emerged in the Neurovascular Unit

  • Roles of CNS microvasculature in the neurovascular unit
  • Innate inflammation
  • Hemostasis in the CNS and role (s) of CNS hemostasis in hemorrhage

Top priorities for future directions:

1. Further understand the components and inter-relationship within the NVU during focal ischemia: Need to further progress in understanding the components of the NVU and the relationships of cerebral microvascular responses to those of the neuropil during focal ischemia. Once thought to be simple conduits of flow, the cerebral microvasculature is now known to be dynamic and pluripotential in its acute and chronic responses to focal ischemia and reperfusion. The CNS microvasculature is unique, and stands as a part of the neurovascular unit; exactly how it differs from other microvessel beds requires further study. How microvascular endothelium and astrocytes communicate with each other, the roles of the intervening ECM, and how these interactions are modified by amyloid deposition, age, and other factors under normoxia and ischemia, provides an exciting avenue of research. This alone is likely to inform new therapeutic directions and explain current research limitations in ischemia, intracerebral hemorrhage, vascular dementia, and amyloid deposition disorders.

2. Study innate inflammation under conditions of health, focal ischemia, and hemorrhage: The role of innate inflammation in the CNS is gaining increased attention, with increased understanding of i) how the peripheral inflammatory network affects the CNS, ii) the early roles of PMN leukocytes, which have been difficult to target, iii) the role of complement components in modulating inflammation, and iv) emerging links between the contact pathway of coagulation and regulation of inflammation and vascular permeability, the role of innate inflammation in the CNS is gaining increasing attention

3. Understand how the brain and its vasculature regulate hemostasis uniquely and the impact of hemostasis in response to injury (focal ischemia and hemorrhage): Further investigation into the unique aspects of the CNS microvasculature, better understanding of the development and maintenance of the permeability barrier, and additional identification of the proteases, receptors, ligands and inhibitors that regulate CNS hemostasis is needed. Such research will help to identify new targets to more safely attenuate coagulation without impairing hemostasis. A better understanding of CNS-specific hemostatic mechanisms (and their link to other processes, e.g. inflammation) is also crucial for identifying new modalities to prevent intracerebral hemorrhage and hematoma expansion, and to best reduce and manage the risk of cerebral hemorrhage in patients on anticoagulants. As well as continuing work on  developing agents to prevent/reduce cerebral hemorrhage, and to reduce the brain injury due to clot-derived factors, there is new interest in modulating hematoma resolution. The latter requires mechanistic understanding of the interaction between the inflammatory system and different proteases in the coagulation and fibrinolytic systems.

Top

EPIDEMIOLOGY AND RISK FACTORS (View the Full Report)

Co-Chairs: Ralph Sacco, Lynda Lisabeth, Brett Kissela 

Members: Heather Fullerton, Philip Gorelick, George Howard, Steve Kittner, Judith Lichtman, Matthew Reeves, Philip Wolf, Dan Woo

NINDS Liaisons: Claudia Moy, Salina Waddy

STROKE PRG 2011 REVIEW REPORT SUMMARY

Epidemiologic research is critical for understanding the public health burden of stroke. Through epidemiologic research, population subgroups at the greatest risk of stroke are identified allowing for the prioritization of future research and funding. High quality observational epidemiologic studies are critical in identifying new associations and relationships which can be translated into the development of interventions to reduce the public health impact of stroke through clinical and behavioral intervention trials. Some of the observed reduction in stroke incidence and mortality, as well as improved outcomes in recent stroke clinical trials, has been attributed to more intensive control of risk factors. A great deal of progress has been made in stroke epidemiology since the last SPRG. Staff identified at least 35 grant awards (23 NINDS, 12 non-NINDS) since 2007 that were related to stroke epidemiology. Advances are summarized in a variety of areas:

  • Common Data Elements (Previous Priority #1) – NINDS initiated a Common Data Element (CDE) project to facilitate the combining of epidemiologic data from multiple sources and studies
  • Linkage between Epidemiological Data and Administrative Data (Previous Priority #1) - Several NIH funded grants are linking population-based epidemiologic studies to Medicare data, allowing for the identification of strokes
  • Stroke Trends (Previous Priority #2) – New epidemiologic data on temporal trends in stroke incidence have been published from the Framingham Heart Study, the Greater Cincinnati-Northern Kentucky Stroke Study, and the Brain Attack Surveillance in Corpus Christi (BASIC)
  • Epidemiologic Training (Previous Priority #3) - Increase in training opportunities in clinical research methodology and epidemiology: at least 6 NINDS T32 programs, 19 K23s, 2 K24s, 4 K02s, and 1 F31 have been funded. SPOTRIAS and R25s have also increased research training.
  • Other advances in areas are outlined including: Stroke Geography, Stroke in Women, Pediatric Stroke, Disparities in Stroke Care, Novel Risk Factors, Vascular Cognitive Impairment, Stroke Genetic Epidemiology, and Translational Epidemiology

New stroke research opportunities, emerging topics, and unresolved areas since 2007 are summarized across a variety of topic areas: Race-ethnic and Geographic Disparities, Eliminating stroke health disparities, Post-stroke Outcomes including Cognition, Stroke in Women including HRT, Pediatric Stroke, Stroke Trends, Novel Risk Factors including Sociocultural factors and subclinical disease, and Epidemiologic Training

Top priorities for future directions:

1. Improve understanding of race and ethnic stroke disparities (TOP PRIORITY): Despite recent successes from NIH-funded studies providing some insights into the causes of these disparities, the understanding of the contributors to these disparities remains insufficient to guide development of interventions. Epidemiologic studies need to focus on specific gaps in our understanding of the risk, determinants and outcomes of stroke in special populations including women, racial and ethnic subgroups, and children, as well as explanation for geographic variability.

2. Evaluate the usefulness of health IT as a tool for epidemiology research: There has been an explosion of electronic health-related data, including large administrative data sets and data collected in electronic medical records, which will become increasingly available for research studies. A major priority in the next 5 years will be to evaluate the validity and effectiveness of these data sources in providing added value to stroke epidemiology and surveillance studies.

3. Translate knowledge from epidemiological studies into improved health: Continued support of epidemiologic stroke studies that monitor trends in stroke burden, fill gaps in knowledge, and discover new associations should be a high priority. Critically, we need to accelerate the translation of the results from epidemiology studies into improved health by informing evidence-based practice recommendations and clinical care, translating findings into behavioral interventions, and providing the fundamental preliminary data needed for randomized clinical trials.

Top

 

GENETICS (View the Full Report)

Co-Chairs: Jonathan Rosand, James Meschia, Andrew Singleton

Members: Cenk Ayata, Mark Cookson, Frank Faraci, Murat Gunel, Sek Katherisen, Jennifer Majersik, Michael Nalls, Stephen Rich, Owen Ross, Dan Woo, Bradford Worrall, Cara Carty, Steve Pavlakis [Comment: Names listed in alphabetical order, except for Carty and Pavlakis who were not full members]

NINDS Liaisons: Katrina Gwinn, Tim LaVaute

STROKE PRG 2011 REVIEW REPORT SUMMARY

There have been advances in several areas over the previous period. There is a general and plausible belief that a key to understanding the genetics of stroke lies in large collaborative genetic analyses. A key limitation in such an endeavor lies in the harmonization of phenotypes and measures across datasets; significant progress has been made in this regard with the development and integration of classification algorithms and large consortia. These consortia and other independent studies have enabled progress in several avenues; first in ischemic stroke, the identification of replicated risk loci at chromosomes 9p21 and 16q22; second, the association of APOE e2 alleles as a risk factor in intracerebral hemorrhage; third, the identification of multiple loci containing risk alleles for intracranial aneurysms; and last, the investigation of mitochondrial DNA variants as a modulator for stroke. In the context of monogenic disease, there has been continued interest and progress in developing cohorts of familial stroke, and given the sibling relative risk of this disease, this is considered an important resource for the future. Likewise considerable progress has been made in testing transfusion therapy in the prevention of stroke in sickle cell disease. There has been an effort to understand the genetics of drug response and this bears direct relevance to stroke with the identification of genetic modifiers of response/tolerance to warfarin, clopidogrel and statins. From an mechanistic perspective, genetics has been used to create animal models of disease with mice carrying targeted mutations in NOTCH3, PPARγ and collagen type IV each recapitulating some of the key features of disease.

There remain several critical challenges in the field of stroke genetics. From a gene discovery standpoint, efforts to identify further risk loci for ischemic stroke, pediatric stroke, and intracerebral hemorrhage each require very large numbers of samples from well-characterized subjects, and the support to pursue modern genetic approaches to gene discovery (high density genotyping, targeted sequencing, whole exome sequencing, whole genome sequencing etc). It will also be important to combine many of these genetic studies with longitudinal collection and biobanking of RNA, serum, plasma, and tissue. These studies will be expensive and time consuming; however they offer the best opportunity to delineate the etiology of these complex diseases and to define biomarkers for risk, prognosis and treatment efficacy. Still in this vein, it is important that genetics is incorporated early into clinical trials; not only to define groups with likely differential outcomes or responses, but also to define risk factors. One area that requires increasing emphasis is the investigation of stroke in underrepresented populations, while difficult studies to initiate and maintain, the varied burden of stroke across diverse populations likely means that it is important to establish the extent and genetic basis of population heterogeneity of this disease.

While the committee noted that substantial hurdles exist to understanding the genetic basis of stroke, we were enthusiastic about the future of this field. Much of the groundwork has been laid, and it is apparent from other complex diseases that many of the proposed strategies work well; thus given appropriate support, these research priorities represent tractable problems over the coming period.

Top priorities for future directions:

1. Promote large, multi-center collaborations to recruit new cases and appropriate controls are needed to build on current work that is utilizing nearly every available sample: New recruitment can effectively address the power/sample size demands of sequencing, the heterogeneity of stroke as a phenotype, and the importance of uniform phenotyping and radiographic and risk factor ascertainment.

2. Develop a mechanism whereby investigators can efficiently engraft parallel pharmacogenomic studies onto NINDS-supported clinical trials meeting appropriate criteria: Pharmocogenomics has the potential to attack the heterogeneity problem that plagues many trials, which dilutes the effects of the experimental treatment and reduces chances of observing a significant difference among treatment groups.

3. Elucidate the mechanisms by which genetic factors modulate the risk and outcome of cerebrovascular disease and stroke: Achieving this goal will critically depend on the development and use of animal models that incorporate newly discovered human genetic factors, while modeling the impact of risk factors, gender and aging, to better mimic the human condition.

Top

HEALTH SERVICES IMPLEMENTATION (View the Full Report)

Co-Chairs: Mark Alberts, Larry B. Goldstein, Amytis Towfighi

Members: Eric Cheng, Edward Jauch, Dana Leifer, David Bruce Matchar, Marilyn Rymer, Linda Williams

STROKE PRG 2011 REVIEW REPORT SUMMARY

The effective implementation of stroke-related advances in medical science remains a top priority as it has the potential to rapidly improve the delivery of care and outcome of patients with cerebrovascular disease. These advances include development of criteria for Stroke Centers, effective EMS triage and diversion, the use of various tele-technologies to extend clinical expertise to underserved regions, and similar system-based changes.

There were few grants specifically addressing the health services implementation (HSI) priorities from the last Stroke PRG. Of those grants identified in the HSI group, many were either training grants or were sub-studies of larger SPOTRIAS projects.

New programs that emphasize ‘pay for performance’ may accelerate the adoption and implementation of best practices for healthcare systems, hospitals, physician groups, individual practitioners, and other healthcare professionals.

Outcome measures and reimbursement should be appropriately adjusted for stroke severity and medical complexity to accurately reflect quality of care.

Top priorities for future directions:

1. Evaluate strategies to improve the identification, treatment and control of vascular risk factors across the spectrum of care: These strategies should include environmental changes and development of effective interventions for improving medication compliance and lifestyle changes. Research programs that determine the causes and remedies for suboptimal risk factor control, including limited access to outpatient care, lack of standardized outpatient performance measures, poor medication adherence and difficulty in instituting lasting lifestyle changes. Improving risk factor control could have far-reaching effects, reducing initial and recurrent strokes rates, improving outcomes, preventing readmissions, and reducing health care costs throughout the spectrum of care.

2. Identify and address barriers to the widespread use of hypothermia to treat post-cardiac arrest patients: Aggressive efforts to identify barriers and limitations to using hypothermia to improve outcomes after cardiac arrest. Considering that this is a class I level I recommendation, it should be widely implemented. This area has the potential to improve outcomes and reduce the utilization of long-term and expensive health care and related resources.

3. Identify strategies to improve patient access to comprehensive rehabilitation services that have been shown to enhance outcomes and quality of life post-stroke: Increasing access to and use of rehabilitation services for post-stroke patients. Although there have been significant advances in rehabilitation services over the past 10 years, they are not uniformly applied nor are they easily accessible to all patients in all parts of the country. Considering the impact that comprehensive post-stroke rehabilitation can have on improving outcomes and improving the quality of life, this is a high impact area of focus.

Top

IMAGING (View the Full Report)

Co-Chairs: Gregory Albers, Ting Lee, Steven Warach

Members: Colin Derdeyn, John Detre, Chelsea Kidwell, Maartin Lansberg, Michael Lev, David Liebeskind, Randolph Marshall, Michael Moseley, William Powers, Howard Rowley, Keith St. Lawrence, Max Wintermark, Ona Wu, Gregory Zaharchuk

NINDS Liaison: Scott Janis

STROKE PRG 2011 REVIEW REPORT SUMMARY

Numerous major advances in stroke imaging research have occurred over the past 5 years. Identification of penumbral tissue using both MRI and CT techniques has markedly advanced. In fact, neuroimaging is now being used for selection, monitoring, and testing of a number of different therapeutic interventions. The last few years have also seen more functional imaging markers being developed that could advance our knowledge of the underlying mechanisms of brain injuries and serve as surrogate outcomes for clinical trials. Molecular and cellular neuroimaging are new technologies being used to define pathophysiologic mechanisms. Because neuroimaging methods are noninvasive and can visualize brain structure and function in both patients and preclinical models, they offer the potential to elucidate mechanisms of recovery and serve as biomarkers for predicting recovery and monitoring treatment responses.

Key initiatives for the future stroke imaging research, in priority order, are:

1) Serial imaging studies from acute to chronic timeframes using multimodal imaging, cerebrovascular reserve studies, and computational modeling to better understand the impact of cerebral hemodynamics, collateral flow, oxygenation, and brain metabolism upon tissue survival and function.

2) Randomized placebo controlled trial of IV tPA beyond 4.5 hours selected by ‘penumbral’ mismatch imaging.

3) Creation of an acute stroke imaging repository including a supporting infrastructure to enhance collaborative research to standardize and validate imaging protocols and processing methods.

4) Determine the most cost-effective imaging work-up for patients with both ischemic stroke and intracerebral hemorrhage based on which modalities lead to treatment decisions that have been proven to affect outcomes.

5) Routine, practical, clinical metabolic imaging (e.g., CMRO2) added to the multimodal acute stroke imaging exam.

6) Investigate imaging markers that reflect injury to large and/or small blood vessels and their consequences.

7) Development of PET ligands and novel imaging techniques to allow imaging of synaptogenesis and other neuroplastic processes in humans.

Top priorities for future directions:

1. Conduct serial imaging studies: Serial imaging studies from acute to chronic timeframes using multimodal imaging, cerebrovascular reserve studies, and computational modeling to better understand the impact of cerebral hemodynamics, collateral flow, oxygenation, and brain metabolism upon tissue survival and function.

2. Conduct imaging-informed trial of late IV tPA application: Randomized placebo controlled trial of IV tPA beyond 4.5 hours selected by ‘penumbral’ mismatch imaging

3. Create acute stroke imaging repository: Creation of an acute stroke imaging repository including a supporting infrastructure to enhance collaborative research to standardize and validate imaging protocols and processing methods.

Top

NEURO-CEREBRO-VASCULAR DEGENERATION (View the Full Report)

Co-Chairs: Eng Lo, David Greenberg, Midori Yenari

Members: Stephen Back, Jun Chen, Rona Giffard, Patricia Hurn, Costantino Iadecola, Paul Rosenberg, Michael Tymianski, Raghu Vemuganti, Berislav Zlokovic

NINDS Liaisons: Francesca Bosetti, Tim LaVaute

STROKE PRG 2011 REVIEW REPORT SUMMARY

Advances:

  • Dissection of cell-cell signaling in the “neurovascular unit” involving crosstalk between neuronal, glial and vascular elements in the CNS.
  • Understanding of crosstalk between the neurovascular unit and systemic responses in the body (non-CNS vascular systems, circulating blood as well as immune systems).
  • Emerging appreciation that neurovascular unit-systemic responses apply not only to stroke, but may also be important for the pathophysiology of dementia and neurodegeneration.

Unresolved Areas and Opportunities:

  • How do non-neuronal responses (e.g. microglia and pericytes) contribute to injury and repair? And do these mechanisms differ in gray vs white matter?
  • How are cellular mechanisms linked to emerging molecular pathways involving mitochondrial energetics, micro RNA (miRNA), and post-translational modifications?
  • How are all these pathways influenced by gender, age and co-existing disease state (co-morbidities), all factors that could impact stroke outcome in patients?
  • Can we use in vivo imaging/optogenetic tools together with genomic/proteomic/metabolomic approaches in novel transgenics to study the entire neurovascular unit simultaneously?
  • Need to understand how responses in the neurovascular unit transition from initial injury during acute stroke into repair and neurovascular remodeling during stroke recovery, as well as neurodegeneration more broadly.

Top priorities for future directions:

1. Develop conceptual framework: Need to better understand how interactions in all elements of the neurovascular unit along with systemic/systemic immune responses underlie the transition from injury into repair after stroke.

2. Develop improved models: Need to build better models (molecular, cellular, animal) that capture pathophysiology as it is influenced by altered neuro-cerebro-vascular baselines (e.g. age, gender, inflammation and other diseased or states).

3. Address translational hurdles: In addition to timing issues that need to be clarified in stroke models, there needs to be a better understanding of how these timelines translate into humans. For example, if neuroprotection is observed within a 6 hour window in rodent stroke, what does that mean in stroke patients? How does dose and timing in rodents translate into humans? What preclinical standards should we expect to see prior to embarking on human studies?

Top

NEUROVASCULAR PROTECTION MECHANISMS (View the Full Report)

Co-Chairs: Patricia Hurn, Kyra Becker, Raymond Swanson

Members: Dennis Choi, Ulrich Dirnagl, Marc Fisher, Mark Goldberg, Louise McCullough, Thaddeus Nowak, Jr, Sean Savitz, Richard Traystman

NINDS Liaisons: Francesca Bosetti, Erik Runko

STROKE PRG 2011 REVIEW REPORT SUMMARY

The working group identified six major research advances related to neurovascular protection, many of which were positively influenced by the SPRG process. One key new opportunity for the field was focused interactions between the injured CNS and the so-called super-systems, particularly the immune system. Five major unresolved areas were identified and analyzed: the fundamental question of whether NvPr is still a useful and productive area of stroke research; the repetitive but unresolved problem that pre-clinical testing of pharmaceutical compounds, biotechnologies or devices remains sub-optimal; the observation that the hypothesis of neurovascular protection has not been tested in clinical trials, the need for new methods to close the gap between bench stroke research and subsequent clinical studies; and the directive that NvPr research cannot be focused solely on brain. Priorities were identified for future stroke research directions: 1) the improvement of the cellular-animal study-clinical trial interface, 2) expansion of our current clinical trial repertoires to include approaches such as specific pathology-focused, exclusive patient trials.

Top priorities for future directions:

1. Improve the cellular-animal study-clinical trial interface: Research topics should consider this interface and the integration of emerging data, rather than disparate directions of inquiry. It is suggested that new funding mechanisms for research in this integrated direction must be developed and implemented.

2. Include an additional approach in our current clinical trial repertoire: Specifically, the field should design highly exclusive trials in patients that are selected by their linkage to data arising from animal models and other experimental systems.

Top

Omics (View the Full Report)

Co-Chairs: Valina Dawson, Mingming Ning, Roger Simon

Members: Alison Baird, Christopher Beecher, Frank Sharp, An Zhou

NINDS Liaisons: Katrina Gwinn, Erik Runko

STROKE PRG 2011 REVIEW REPORT SUMMARY

‘Omics refers to both unbiased and targeted, high throughput large scale analysis of biologic samples with the most developed technologies being applied to genomics and proteomics. Metabolomics is a later entry to the Omics approach but the technology is rapidly developing. For the purpose of this report we focus on Genomics/transcriptomic, Proteomics and Metabolomics as applied to Stroke research.

In the Genomics field increased availability, reduced base costs, standardization of analysis software and approaches and improved annotation has permitted application of this ‘Omic approach to clinical stroke research leading to a number of important advances made in the field of stroke. Research teams have shown differential gene expression in ischemic stroke subtypes showing that different types of stroke and causes of can be differentiated. These findings reveal potential for new diagnostic tools that could improve the treatment of stroke patients. Additionally studies comparing human and animal models have shown similarities suggesting the relevance of animal models to human disease. The technology applied to Genomics is advancing from microarray approaches to elegant next generation and deep sequencing strategies. To take advantage of these new approaches there will be a need for quantitative biologists to analyze and manage large data sets and the need for access to human material as the power of these technologies is in the number of samples that can be analyzed.

Proteomics was an emerging field when the SPRG was first initiated. Over 10 years it has rapidly evolved and developed as a technology – making important progress in stroke basic and pre-clinical research and now just entering the translational and clinical realm. A step closer to the ultimate phenotypic expression, proteomics has advanced from characterizing protein numbers to more sophisticated protein-protein interactions in order to probe important mechanistic questions. Emerging methodology to surveying the proteome in real time to distinguish confounding biological noise from important primary death and survival pathways are important next steps. In the future, application of proteomics technology holds enormous potential for unmet needs in stroke by understanding the biological significance of post-translational modifications, dissecting subproteomic/organelle interactions, and quantifying the precise stoichiometry of cellular metabolism, in order to investigate cellular mechanistic interactions and accurately monitor and triage therapeutic responses.

Metabolomics is in the true sense an ‘Omic approach in development and currently at the stage where Genomics and Proteomics were 10-15 years ago. However, considering the acute and chronic metablolic changes that occur during and following stroke, it may be a most revealing technology when applied to stroke studies. There is tremendous promise in significantly understanding how metabolic dysfunction leads to pathologic processes as well as developing new tools for diagnosis of different types of stroke and monitoring the efficacy of therapeutic intervention in the field of metabolomics. The limiting factors at this time are access to the technologies, standardization and the current cost of entry to this ‘Omic field.

In summary the promise of ‘Omic technologies has been realized in some contexts and continues to be developed in others. The new challenges revolve around analysis and handling of very large data sets and access to clinical samples with sufficient power to derive meaningful conclusions. The use of these technologies has moved from basic science studies to translational and clinical research with the promise of development of clinical diagnosis and therapeutic monitoring.

Top priorities for future directions:

1. Facilitate access and cross-talk of genomic/transcriptomic, proteomic, metabolomic and bioinformatics technology and develop methods for interaction and standardization of design, data analysis, and interpretation related to stroke. Promoting functional studies harnessing advances in multiple ‘Omics strategies are exciting and promising areas of exploration for the next decade.

2. Create a platform for defining stroke at a molecular and mechanistic level. This should include the creation of methods and protocols for the collection of biological samples for ‘Omic studies with access to biospecimens linked to current and future National Institutes of Health (NIH) trials. With basic research as a template, identify molecular markers or profiles of stroke and stroke risk in patients.

3. Recruit geneticists and molecular biologists into collaborations with stroke researchers (both clinical and basic science), with the objective of achieving near-term progress in capitalizing on current technologies. In parallel, enhance the recruitment of young and mid-career scientists into existing training programs.

Top

PREVENTION OF FIRST AND RECURRENT STROKE (View the Full Report)

Co-Chairs: S. Claiborne Johnston, Karen Furie, Bruce Ovbiagele

Members: Marc Chimowitz, Mitchell Elkind, Heather Fullerton, Scott Kasner, Walter Kernan, Laura Sauerbeck, Barbara Vickrey

NINDS Liaisons: Scott Janis, Salina Waddy

STROKE PRG 2011 REVIEW REPORT SUMMARY

In the last 5 years, measured progress has been made in research on prevention of first and recurrent stroke. Among other advances, several major clinical trials have helped to clarify appropriate antiplatelet use, the role of stenting in carotid and intracranial atherosclerosis, and brought new, safer and more effective anticoagulants to the market for stroke prevention in patients with atrial fibrillation. Several of the prior recommendations of this Stroke PRG subgroup were implemented or will come on line soon, including NEURO-NEXT and a U54 for stroke prevention research centers. The committee identified particularly exciting opportunities in five areas: population-based primary stroke prevention, perinatal stroke prevention, personalized stroke prevention, plaque hemorrhage and rupture, and technology as a tool to enhance patient and physician adherence. In addition, three priorities were recommended:

Top priorities for future directions:

1. Improve implementation research: Improve implementation of existing, proven stroke prevention interventions by: (1) identifying barriers to such implementation by assessing the individual, healthcare providers, and the healthcare system, (2) studying methods of overcoming these barriers, including through technologies, systems-based interventions, and incentives, and (3) supporting the development of research evaluating the effectiveness of innovative initial and recurrent stroke prevention interventions, especially in underserved populations and minority racial/ethnic groups.

2. Conduct risk factor assessment and risk prediction: Track the prevalence and impact of stroke risk factors in the US, and develop and examine the effectiveness of quantitative risk factor assessment tools that can identify stroke-prone individuals who need aggressive risk factor management and recurrent stroke prevention intervention, with particular emphasis on underserved populations and minority racial/ethnic groups.

3. Support and evaluate innovative prevention strategies: Support research designed to identify and evaluate innovative stroke prevention treatments and strategies, with particular attention to dietary, lifestyle, and population-directed interventions that are inexpensive and cost-effective.

Top

RECOVERY AND REHABILITATION (View the Full Report)

Co-Chairs: Steve Cramer, Pam Duncan, Anna Barrett

Members: John Chae, Leonardo Cohen, Bruce Crosson, Leigh Hochberg, Rebecca Ichord, Albert Lo, Randy Nudo, Randall Robey, R. Jarrett Rushmore, Sean Savitz, and Robert Teasell with assistance from Norine Foley

NINDS Liaisons: Francesca Bosetti, Daofen Chen, Scott Janis

STROKE PRG 2011 REVIEW REPORT SUMMARY

Recovery of function after stroke arises on the backbone of biological events that are therapeutic targets. Thus preclinical studies and early human clinical trials have provided evidence for a large number of potential therapies to improve patient outcomes after stroke, including cell-based therapies, drugs new and old, a host of devices, cognitive approaches, and activity-based approaches.

Recovery of function after stroke also involves many factors that extend beyond brain biology, factors that distinguish us as humans, such as social role, family role, vocational competence, participation in sports and leisure, affective state, and more.

Most strokes affect many neural systems in parallel. Thus the most robust understanding of the stroke impact and restorative therapy effects is obtained by considering the individual components of a stroke such as effects on attention, balance, coordination, executive function, speech and language, memory, mobility, motor function, pain, mood, sexual function, somatosensory function, spatial cognition, swallowing, vision, and more.

Understanding stroke recovery requires modality-specific endpoints. Many preventative, reperfusion, and neuroprotective therapies treat the brain as a single target. In contrast, therapies that target stroke recovery must treat the brain as a collection of injured neural systems, some of which are potential therapeutic targets and some of which are not. Global outcome measures, while of sure value in stroke, may lack the granularity to resolve some of these important distinctions.

During the weeks following a single stroke, patients often are moved from one setting to the next, receiving care from numerous providers along the way. Maximum attention to the continuity of care can improve behavioral outcomes and also reduce medical complications.

Substantial data exist as to how to maximize stroke rehabilitation effects, but this information is often incompletely applied in practice. This could be improved with healthcare policy research and reform.

Stroke in children differs from stroke in adults in numerous ways from pathogenesis to developmental state at time of injury. A number of major questions remain in stroke recovery and rehabilitation among children, who have the largest number of lifetime years affected by stroke.

There have been few human drug or cell-based trials targeting stroke recovery despite many promising preclinical study results. Calls are needed for specific NIH-directed mechanisms targeting the successful translation of novel drug and biological therapies from animals to stroke patients. More resources should be applied to implementing and directly supporting the recommendations of the SPRG if the enormous potential of recovery and rehabilitation interventions is to be realized.

Top priorities for future directions:

1. Understand and harness clinical brain plasticity: A need exists for improved methods to measure brain plasticity after stroke. Studies identifying valid, reliable, affordable, and accessible measurements of neuroplasticity, both functional and structural, are thus needed. New methods are emerging that have great promise in this regard but require further study to realize their full potential. Measures of neuroplasticity in the lesioned brain should be better validated with outcomes of high clinical priority that include functional recovery, and, as possible, return to activities of daily living or reinsertion into work environments. A better understanding is needed regarding how these measures of brain plasticity can be used to guide and individualize rehabilitation/restorative therapies in order to achieve best patient outcomes. Issues specific to the aging or the developing brain are important to consider in order to achieve maximum effect across all persons affected by stroke.

2. Understand the experience-dependent nature of post-stroke plasticity: Substantial data suggest that brain plasticity after stroke, whether spontaneous or treatment-induced, is shaped by experience. This feature distinguishes restorative therapies from other classes of stroke therapy such as prevention, reperfusion, and neuroprotection. Studies are critically needed to understand which experiences are most important, what dose of experience is needed to maximize outcomes, and how to measure these experiences, bearing in mind that in this context, experience includes standard therapies such as speech therapy or physiotherapy as well as psychological and socioeconomic issues. These goals may be aided by an improved understanding of biomarkers of recovery and restorative therapies.

3. Translate restorative post-stroke therapies: The burgeoning knowledge base in the basic science of post-stroke brain repair suggests an enormous opportunity for translating new restorative therapies in humans who otherwise would be destined to years of post-stroke disability. Increased knowledge is needed on many fronts to successfully translate these findings, such as how to match the right patients with the right therapies, how to generalize therapeutic effects across differences such as in age and gender, choice of biomarkers to maximize translation of restorative therapies; and how to combine therapies once each is better understood individually. Successful translation of stroke recovery therapeutics must be seen as a team effort, from bench to bedside to health policy reform, for delivery of appropriate treatment. To advance restorative therapy trials in humans, implementation of Specialized Programs of Translational Stroke Research in Recovery (SPOTS-R2), akin to the SPOTRIAS Centers that were created to foster acute stroke care, are a priority.

Top

VASCULAR COGNITIVE IMPAIRMENT (View the Full Report)

Co-chairs: Steven Greenberg, Sandra Black, Philip Gorelick

Members: Cenk Ayata, Hugues Chabriat, Chelsea Kidwell, Jin-Moo Lee, Vincent Mok, David Nyenhuis, Bruce Reed, Gary Rosenberg, John Sled, Eric Smith

NINDS Liaison: Thomas Jacobs

STROKE PRG 2011 REVIEW REPORT SUMMARY

Top Research Advances since 2007

Animal Models

  • New and better transgenic models of CADASIL and CAA
  • New experimental systems for studying chronic brain ischemia
  • New noninvasive neuroimaging tools, with potential for human translation

Novel Human Biomarkers

  • Incorporation of neuroimaging into VCI diagnostic criteria
  • Expanded focus on cerebral microbleeds and microinfarcts as key markers
  • ß-amyloid imaging for detection of plaque (AD) and vascular (CAA) amyloid
  • Newly identified genetic causes of hereditary VCI

Outcome Markers and Clinical Trial Design

  • Improved VCI trial outcome markers
  • New clinical trial data on VCI prevention
  • New data on symptomatic treatments applied to VCI

Opportunities, Emerging Topics, and Key Challenges

Animal Models

  • Translational potential of animal models still limited and unproven.
  • The SHR/SP spontaneously hypertensive/stroke prone rat may be underutilized.

Novel Human Biomarkers

  • Insufficient studies of VCI imaging across racial/ethnic/demographic groups.
  • Most clinically meaningful VCI imaging biomarkers still not established.
  • Emerging methods for measuring small vessel integrity/function and detecting chronic microinfarcts appear promising.

Outcome Markers and Clinical Trial Design

  • VCI prevention may be achievable with existing methods, but hard to demonstrate practically, e.g. if long-term treatment is required.
  • Potential strategies might be to perform VCI prevention trials using high-risk groups or to build them on top of ongoing acute stroke trials.

Top priorities for future directions:

1. Develop animal models: Continue to seek animal models that mimic the range of tissue damage of human VCI (white matter lesions, lacunar infarcts, microinfarcts, microbleeds) in the setting of common vascular risk factors (age, hypertension, diabetes). Develop noninvasive tools for detecting the key molecular and cellular pathways and translating to human trials.

2. Develop novel human biomarkers: Fully incorporate ß-amyloid imaging into studies of VCI, and small vessel-related neuroimaging markers into studies of AD, recognizing that mixed cognitive impairment/dementia is very common. Focus future biomarker development on markers of small vessel disease severity and location, integrating these into multimodal studies of existing imaging markers, biochemical and genetic risks, and epidemiologic factors (including variations related to racial/ethnic/demographic group), aimed ultimately at unraveling the precise connections between vascular pathology, neurodegenerative pathology, and neurological impairment.

3. Develop outcome markers and clinical trial design: Develop large-scale clinical trials of dementia-free subjects with substantial small vessel disease for intensive vascular risk factor modification versus usual vascular risk factor modification for the prevention of cognitive impairment or dementia. Incorporate VCI biomarkers (e.g. structural MRI, novel vascular imaging methods, and ß-amyloid detection) as well as recent advances in neuropsychological and functional outcome measures into such trials.

Top

SPRG Final Review participants

ACUTE ISCHEMIC STROKE TREATMENT
Co-Chairs
: Jeffrey Saver, Helmi Lutsep, Patrick Lyden
Members: William Barsan, Kyra Becker, Gabrielle DeVeber, Jeff Frank, Kama Guluma, Clarke Haley, Michael Hill, Reza Jahan, Pooja Khatri, Tom Kwiatkowski, Brett Meyer, Raul Nogueira, Larry Wechsler
NINDS Liaison: Scott Janis

BIOLOGY OF REPAIR
Co-Chairs
: Michael Chopp, S. Thomas Carmichael, Jack Parent
Members: Steven Cramer, Theresa Jones, Randolph Nudo, Sean Savitz, Gary Steinberg, Raghu Vemuganti, Zheng Gang Zang
NINDS Liaisons: Francesca Bosetti, Tim LaVaute

CEREBROVASCULAR BIOLOGY AND NEUROVASCULAR UNIT
Co-Chairs
: Costantino Iadecola, Marilyn Cipolla, Frank Faraci
Members: Nabil Alkayed, Robert Bryan, Turgay Dalkara, Donna Ferriero, Edith Hamel, Zvonimir Katusic, Raymond Koehler, Charles Leffler, Chris Schaffer, Danica Stanimirovic
NINDS Liaisons: Thomas Jacobs, Erik Runko

CLINICAL TRIALS
Co-Chairs
: Joseph Broderick, Thomas Brott, Karen Johnston
Members: Colin Derdeyn, Pam Duncan, Nicole Gonzales, Yuko Palesch, Rema Raman, Robert Silbergleit, Tanya Turan, Kenneth Cavanaugh (reviewer), Natalie Getzoff (reviewer)
NINDS Liaisons: Scott Janis, Claudia Moy, Salina Waddy

CNS HEMORRHAGE
Co-Chairs
: Stephan A. Mayer, Neil Martin, Jaroslaw Aronowski
Members: E Sander Connolly, Nestor Gonzalez, Dan Hanley, J. Claude Hemphill, Richard Keep, Loch MacDonald, Adnan Qureshi, Lauren Sansing, Paul Vespa, Jeff Weitz, William - Young
NINDS Liaisons: Tom Jacobs, Scott Janis

COAGULATION, HEMOSTASIS, AND ENDOTHELIAL CELL INTERACTION
Co-Chairs
: Gregory J. del Zoppo, Maiken Nedergaard, David J. Pinsky, Jeffrey Weitz
Members: Ulrich Dirnagl, Paula Dore-Duffy, Peter Gross, Antoine Hakim, John Hallenbeck, Richard Keep, James Morrissey, Bruce Ransom, Marc Simard, Lydia Sorokin
NINDS Liaison: Thomas P. Jacobs

EPIDEMIOLOGY AND RISK FACTORS
Co-Chairs
: Ralph Sacco, Lynda Lisabeth, Brett Kissela
Members: Heather Fullerton, Philip Gorelick, George Howard, Steve Kittner, Judith Lichtman, Matthew Reeves, Philip Wolf, Dan Woo
NINDS Liaisons: Claudia Moy, Salina Waddy

GENETICS
Co-Chairs
: Jonathan Rosand, James Meschia, Andrew Singleton
Members: Cenk Ayata, Mark Cookson, Frank Faraci, Murat Gunel, Sek Katherisen, Jennifer Majersik, Michael Nalls, Stephen Rich, Owen Ross, Dan Woo, Bradford Worrall, Cara Carty, Steve Pavlakis
NINDS Liaisons: Katrina Gwinn, Tim LaVaute

HEALTH SERVICES IMPLEMENTATION
Co-Chairs
: Mark J. Alberts, Larry B. Goldstein, Amytis Towfighi
Members: Eric Cheng, Edward Jauch, Dana Leifer, David Bruce Matchar, Marilyn Rymer, Linda Williams

IMAGING
Co-Chairs
: Gregory Albers, Ting Lee, Steven Warach
Members: Colin Derdeyn, John Detre, Chelsea Kidwell, Maartin Lansberg, Michael Lev, David Liebeskind, Randolph Marshall, Michael Moseley, William Powers, Howard Rowley, Keith St. Lawrence, Max Wintermark, Ona Wu, Gregory Zaharchuk
NINDS Liaison: Scott Janis

NEURO-CEREBRO-VASCULAR DEGENERATION
Co-Chairs
: Eng Lo, David Greenberg, Midori Yenari
Members: Stephen Back, Jun Chen, Rona Giffard, Patricia Hurn, Costantino Iadecola, Paul Rosenberg, Michael Tymianski, Raghu Vemuganti, Berislav Zlokovic
NINDS Liaisons: Francesca Bosetti, Tim LaVaute

NEUROVASCULAR PROTECTION MECHANISMS
Co-Chairs
: Patricia Hurn, Kyra Becker, Raymond Swanson,
Members: Dennis Choi, Ulrich Dirnagl, Marc Fisher, Mark Goldberg, Louise McCullough, Thaddeus Nowak, Jr, Sean Savitz, Richard Traystman
NINDS Liaisons: Francesca Bosetti, Erik Runko

Omics
Co-Chairs
: Valina Dawson, Mingming Ning, Roger Simon
Members: Alison Baird, Christopher Beecher, Frank Sharp, An Zhou
NINDS Liaisons: Katrina Gwinn, Erik Runko

PREVENTION OF FIRST AND RECURRENT STROKE
Co-Chairs
: S. Claiborne Johnston, Karen Furie, Bruce Ovbiagele
Members: Marc Chimowitz, Mitchell Elkind, Heather Fullerton, Scott Kasner, Walter Kernan, Laura Sauerbeck, Barbara Vickrey
NINDS Liaisons: Scott Janis, Salina Waddy

RECOVERY AND REHABILITATION
Co-Chairs
: Steve Cramer, Pam Duncan, Anna Barrett
Members: John Chae, Leonardo Cohen, Bruce Crosson, Leigh Hochberg, Rebecca Ichord, Albert Lo, Randy Nudo, Randall - Robey, R. Jarrett Rushmore, Sean Savitz, and Robert Teasell with assistance from Norine Foley MSc
NINDS Liaisons: Francesca Bosetti, Daofen Chen, Scott Janis

VASCULAR COGNITIVE IMPAIRMENT
Co-chairs
: Steven Greenberg, Sandra Black, Philip Gorelick
Members: Cenk Ayata, Hugues Chabriat, Chelsea Kidwell, Jin-Moo Lee, Vincent Mok, David Nyenhuis, Bruce Reed, Gary Rosenberg, John Sled, Eric Smith
NINDS Liaison: Thomas Jacobs

Top

Last updated March 10, 2014