The Aneurysm and AVM Foundation is pleased to announce the recipients of the 2016 Cerebrovascular Research Grant Awards. We selected three researchers (two grants) whose scientific projects showed the greatest potential to improve our understanding of cerebrovascular diseases.
Research Study: An Investigation of Epoxyeicosatrienoic Acids as a Treatment Strategy to Improve Glymphatic Flow, Cerebral Blood Flow and Behavioral Outcomes Following Subarachnoid Hemorrhage in Rats
Primary Investigator: Tristan Stani, MD, Dept. of Neurological Surgery at Oregon Health and Science University
Background: Aneurysmal subarachnoid hemorrhage (SAH) remains one of the most challenging stroke syndromes facing today's neurological critical care providers and surgeons. Despite advances in characterizing the anatomical details of aneurysms and the continued development of novel surgical and endovascular techniques for securing aneurysms, the delayed consequences of initial aneurysm rupture continues to challenge care providers, We continue to lack a sophisticated understanding of the exact systems that are disrupted following SAH and the mechanisms that underlie their dysfunction. All too often the most technically successful treatment of a ruptured aneurysm is unfortunately marred by the delayed stroke and other cerebral dysfunction for which we have limited treatment options
Research Objective: The central objectives of this project are to determine the effectiveness of augmented levels of epoxyeicosatrienoic acids on rescuing perivascular flow of CSF through the glymphatic system in the setting of subarachnoid hemorrhage and to correlate post-SAH changes in the glymphatic system and subsequent glymphatic flow rescue by epoxyeicosatrienoic acids with post-SAH cerebral blood flow changes and behavioral outcomes.
The “glymphatic system” is a cerebral microcirculation system of cerebral spinal fluid (CSF) that has only recently been described. Initial work on this system has suggested important connections with neurodegenerative diseases such as Alzheimer’s Disease. Importantly, the system has also recently been demonstrated to be disrupted following SAH and then restored after the delivery of tPA, a “clot-busting” drug commonly given in the clinical setting following acute ischemic stroke. This suggests important new treatment strategies for SAH.
Outcomes: With funding from The Aneurysm and AVM Foundation, Dr. Stani will launch a series of MRI imaging experiments which will characterize glymphatic CSF flow pre- and post-SAH. He will then image glymphatic flow pre and post-SAH in an experimental group pretreated with analogs to epoxyeicosatrienoic acids (EETs). EETs are endogenous molecules that the body already makes which possess profound anti-inflammatory, vasodilatory and fibrinolytic effects. He hopes to demonstrate that the fibrinolytic ("clot-busting") effects of EETs analogs will improve glymphatic CSF microcirculation and ultimately improve cerebral blood oxygen delivery and decrease cerebral inflammation following SAH, which will ultimately lead to improved outcomes.
Source: Tristan Stani, MD, Oregon Health and Science University. This research summary has been adapted and edited from Dr. Stani's research proposal.
Research Study: Quality of Life in Patients Diagnosed with Unruptured Cerebral Aneurysm: Prospective Single-Center Series
Co-Primary Investigators: Peter Gooderham, MD, Clinical Assistant Professor, Division of Neurosurgery, Dept. of Surgery at the University of British Columbia and Charlotte Dandurand, MD, Neurosurgery Resident at the University of British Columbia
Background: In the United States, 6 million people, 2% of the population, are living with an unruptured brain aneurysm. Many of these people are unaware of their diagnosis. The most important and devastating consequence of a brain aneurysm is subarachnoid hemorrhage from aneurysm rupture. Living with the diagnosis of an unruptured cerebral aneurysm can understandably cause anxiety for a patient and the impact on patients' quality of life is not well understood. The degree to which this diagnosis affects patients and how this affect changes over time remains unknown. The impact of microsurgical clipping and endovascular coiling on patients' quality of life is also poorly studied
Research Objective: The objective of this research is to identify how the diagnosis of an unruptured cerebral aneurysm and its subsequent treatment impacts quality of life over time.
Outcomes: With funding from The Aneurysm and AVM Foundation, Dr.'s Gooderham and Dandurand will use objective quality of life tools to interview patients at diagnosis and again one year later. Quality of life will be assessed at diagnosis, at 6-12 weeks post-operative follow-up, and at 1 year post-operative follow-up in patients who have been treated. The latter group will be divided into 2 sub-groups, endovascular and microsurgical (clipping). Patient demographics, size and location of aneurysm, radiological features, presence and degree of neurological deficits, treatment modalities, and postoperative complications will also be collected.
Source: Charlotte Dandurand, MD, University of British Columbia. This research summary has been adapted and edited from Dr.'s Gooderham and Dandurand's research proposal.
Primary Investigator: Jennifer Frontera, MD, FNCS (Associate Professor of Medicine (Neurology) Cleveland Clinic Lerner College of Medicine and Case Western Reserve University)
Co-Investigators: Thomas M. McIntyre, PhD (Staff Cellular & Molecular Medicine Professor, Molecular Medicine, Cleveland Clinic), Jose Javier Provencio, MD (Assistant Professor of Medicine, Staff Neurointensivist, Cleveland Clinic), Amy S. Nowacki, PhD (Assistant Staff Biostatistician, Cleveland Clinic)
Background: Subarachnoid hemorrhage (SAH) is one of the most devastating forms of stroke. Currently, the most important predictor of how a patient will function after SAH is the early brain injury that occurs at the time of rupture, yet little is known about just how that happens and no therapeutic treatments for acute brain injury are currently available. Dr. Frontera and her team found that platelets become activated after SAH and form aggregates with leukocytes (or small obstructions), which may lead to ischemia acutely after aneurysm rupture. This sequence of events may be responsible, in part, for early brain injury.
Research Objective: The central hypothesis of this project is that platelet activation occurs immediately in SAH, leading to the formation of platelet-leukocyte aggregates, obstruction of the microcirculation, and consequent acute brain injury; and inhibition of platelet activation will lesson this pathogenic process.
The objective ofthisprojectistodetermineifSAH patients will have higher markers of platelet activation and platelet-leukocyte aggregates compared to controls,andthatpoorgradeSAH patientswillhavehighermarkerscomparedtoSAH patients with better admission neurological exams or controls. The expectation is then that platelet-leukocyte aggregates will be weakened by aspirin use.
Outcomes: If it is found that activation of platelets and platelet-leukocyte aggregation are associated with worse early neurological status (implying acute brain injury) and worse long term neurological function after SAH, this would suggest that therapeutic interventions that weaken platelet activation and platelet-leukocyte aggregation might be clinically useful. Identifying the mechanism of acute brain injury after SAH is essential to targeting novel therapeutic interventions. Physicians will be able to both suggest therapies to intervene and lessen a patient’s likelihood of additional stroke as well as better predict the outcome for a patient after SAH.
Research Study: Rapid Quantification of Aneurysm Flow and Device-Induced Flow Changes for Real-Time Analysis during Treatment
Primary Investigator: Aichi Chien, PhD (Assistant Professor of Radiological Sciences at UCLA)
Co-Investigators: Fernando Viñuela, MD (Director of the Rigler Radiology Animal Research Center, Professor of Radiology at UCLA), Gary R. Duckwiler, MD (Professor of Radiology at UCLA, Director of Interventional Neuroradiology)
Background: Aneurysms that occur in certain locations are difficult to treat by surgical clipping and large and wide-neck aneurysms cannot be completely occluded with endovascular coils. Recently a new type of interventional device–the flow-diverting stent (FDS)–was introduced to help prevent aneurysm rupture. However, clinical results have shown considerable variation in FDS treatment outcome as well as procedure-related complications. It is currently unclear why FDS treatment is effective in some cases and not in others. There is a powerful need to understand why these complications occur and improve patient selection to reduce complication rates. Assessing how these devices achieve this goal requires studying information related to aneurysm blood flow.
Research Objective: The objective of this project is to develop a quantitative tool to measure aneurysm blood flow which works directly with routinely-collected 2D digital subtraction angiography (DSA) images. The central hypothesis of this project is that quantitative aneurysm flow measurements can be relevant to FDS treatment selection and outcome.
Outcomes: Developing a quantitative tool to measure injected contrast agent flow, we expect to extract a wealth of blood flow dynamic information, allowing us to study flow-related risk properties, specifically, aneurysm flow impingement, pulsatility, pressure, and flow reduction provided by treatment. This quantitative flow measurement tool will provide physicians with currently inaccessible, objective, and reproducible flow information with which to make informed treatment decisions.
These findings may be immediately relevant to clinical treatment of aneurysms, by explaining flow mechanisms underlying FDS outcome and complications. This may lead to decreased FDS treatment related complications by encouraging certain types of aneurysms to be excluded from FDS treatment.
In the future, this method will be applied to study or develop new aneurysm treatment devices and will facilitate very large scale, multi-center aneurysm research. The eventual availability of real-time flow information during treatment will further improve device deployment, reducing patient mortality, the occurrence of stroke, and other complications.
The Aneurysm and AVM Foundation is pleased to announce the recipients of 2012 Cerebrovascular Research Grant Awards. We selected three awardees whose scientific projects showed the greatest potential to improve our understanding of cerebrovascular diseases. One grant is named in memoriam for Nancy Quinnine, RN for her tireless efforts on behalf of patients with AVM*.
Research Study: Early inflammation and long-term cognitive outcome after aneurysmal subarachnoid hemorrhage
Principal Investigator: J. Javier Provencio, MD
Research Study: Endovascular biopsy: Evaluation of technical feasibility and assessment of molecular risk factors within cerebral aneurysms
Principal Investigator: Daniel Cooke, MD
Research Study: The role of PDGF-BB/PDGFR-beta signaling in the vascular integrity and therapy of brain AVM*
Principal Investigator: Hua Su, MD
Nancy Quinnine was a dedicated nurse, and founding member of TAAF. She brought 30 years of nursing experience to UCSF and The Aneurysm and AVM Foundation, with the last 11 years devoted to work as part of the UCSF Center for Cerebrovascular Research at UCSF (http://avm.ucsf.edu), where she played a pivotal role as clinical coordinator.
In 2002, she helped organize The Aneurysm and AVM Support Group at UCSF, which continues to meet monthly. She served on the Medical Advisory Board for Ikana Media, creating a Website: Understanding Health. Above all else, her commitment to this patient population spoke for itself. Nancy worked tirelessly, and with endless enthusiasm and optimism to further research, and empower patients in their own
Research Study: Gene Expression Profiling in Brain AVM Patients
Principal Investigator: William L. Young, MD
Patients with brain arteriovenous malformations (AVM) are at high risk for a kind of stroke called intracranial hemorrhage, which is due to bleeding from ruptured blood vessels, and can cause disabling symptoms or death. Identifying genes involved in the disease process may be clinically useful if able to identify those at highest risk for bleeding, and therefore aid in treatment decisions.
We examined the pattern of gene expression in blood (i.e., gene expression profile) from 40 brain AVM patients (20 ruptured and 20 unruptured) and 20 healthy controls to determine if the expression patterns differ between groups. We observed that gene expression profiles of unruptured brain AVM patients are different from healthy controls, and are markedly different from ruptured brain AVM patients. Genes that were different between the groups were overrepresented in several functional pathways of interest, including inflammatory and growth factor-related signaling pathways.
This first study of gene expression profiling in the blood of brain AVM patients indicates this approach may aid in the discovery of markers to detect individuals at risk for hemorrhage, and provide clues as to the key players in brain AVM. By identifying markers that could signal high risk of having a stroke in the future, we will be better be able to recommend treatment to those who need it the most urgently, or conversely, more rationally defer treatment when appropriate.