The Aneurysm and AVM Foundation is pleased to announce the recipients of the 2019 Cerebrovascular Research Grant Awards. We selected two researchers whose scientific projects showed the greatest potential to improve our understanding of cerebrovascular diseases.
Research Study: Human Genetics and Molecular Mechanisms of Vein of Galen Malformation
Primary Investigator: Kristopher Kahle, MD, PhD., Assistant Professor of Neurosurgery, Pediatrics, and Cellular & Molecular Physiology, Yale School of Medicine; Yale-Rockefeller NIH Center for Mendelian Genomics; Director, Developmental Anomaly Neurosurgery, Yale-New Haven Hospital
Background: Vein of Galen malformation (VOGM) is one of the most common and devastating forms of arteriovenous malformations (AVMs) in children. Despite advances in treatment in recent years, VOGM still frequently leads to heart failure, cerebral fluid imbalance, bleeding within the brain, and even death among affected children. Beginning in infancy, many children undergo multiple surgeries, scans, and invasive procedures, all of which cause enormous physical, emotional, and financial strain on patients and their families.
Very little is known about the causes of VOGM. This lack of knowledge has hindered the development of new and improved methods to diagnose and treat this disease. These obstacles can be overcome using whole exome sequencing (WES), an approach that has led to unprecedented gene discoveries in other structural brain disorders.
He hypothesizes that mutations in interacting components of an EPHB4 signaling network contribute to VOGM by disrupting RASA1/mTORC1-dependent arteriovenous specification. Furthermore, Dr. Kahle hypothesizes that phenotypic heterogeneity and incomplete penetrance of VOGM and variable expressivity may be explained by the compound effect of inherited germline mutation and with tissue-specific somatic mutations.
Research Objective: The goal of Dr. Kahle’s research is to fill these knowledge gaps using the latest in DNA-sequencing technology. Utilizing the power of social media, Dr. Kahle has connected with and recruited patients from around the globe to participate in his genetic study creating the largest cohort of VOGM patients to date. He expects to expand that VOGM case-parent cohort, more than doubling his initial study. He also expects to screen for known VOGM-associated mutations as well as carry out whole exome sequencing and bio-informatic analysis. Finally, Dr. Kahle expects to analyze somatic vascular tissue from germline-mutant VOGM patients for superimposed somatic mutations.
Outcomes: With funds from The Aneurysm and AVM Foundation, Dr. Kahle believes that his approaches will expand the current understanding of how VOGM develops at the molecular level. He hopes that the resulting advances will improve disease management, surveillance, and genetic counseling, stimulate research into new diagnostic and therapeutic options, and improve social support for patients and families afflicted with VOGM and possibly other brain and systemic AVMs.
Included in Dr. Kahle's award is the Lauren Karafiol Cerebrovascular Research Grant. As part of TAAF's part of annual grant program, this award is made in memory of Lauren P. Karafiol and aims to off-set costs of research in the area of AVMs, the disease that forever changed Lauren's life and that of her family. We are incredibly proud to join Lauren's family in support of novel research of arteriovenous malformations.
Source: Kristopher Kahle, MD, PhD, Yale University School of Medicine. This research summary has been adapted and edited from Dr. Kahle’s research proposal.
Research Study: Patient-specific Genetics of Cerebral Aneurysm Endothelium
Primary Investigator: Michael R. Levitt, MD, Associate Professor of Neurological Surgery and Radiology, University of Washington. Dr. Levitt holds several other titles with UW, chiefly Scientific Director of the Stroke and Applied Neuroscience Center.
Background: Cerebral aneurysm formation, growth and rupture occur as a result of forces of blood flow on the endothelial cells that line the arteries in the brain. These forces, called “hemodynamic stresses,” can be calculated from computer simulations, but their effects on endothelial cells cannot be determined in actual patients. In fact, a major drawback of existing CFD (computational fluid dynamics) studies in clinical applications (such as risk of aneurysm growth or rupture, or outcome of aneurysm treatment) is that they do not directly measure the pathological effects of hemodynamic variables on biological tissue. Rather they inferred from a variety of sources such as animal studies and in vitro experiments. The current state of the art cannot provide clinicians with the ability to measure the cellular response of the cerebrovascular endothelium to hemodynamic stress in a specific patient’s cerebral aneurysm, which is a significant gap in knowledge.
To address this critical knowledge gap, and to better characterize the effect of hemodynamic stress on aneurysm endothelial cells, Dr. Levitt’s research will use 3D-printed models of patient’s cerebral aneurysms, which are coated with living human endothelial cells and exposed to hemodynamic stress. The genetic and protein response of these cells to different amounts of hemodynamic stress will be measured.
Research Objective: The goal of Dr. Levitt’s research is to further our understanding of the patient-specific hemodynamic, genetic, and proteomic factors that contribute to aneurysm formation, growth, rupture, and healing thus informing treatment decision-making and improving the quality of life for patients suffering from intracranial aneurysms.
Outcomes: With funds from The Aneurysm and AVM Foundation, Dr. Levitt believes that his translational approach bridges the gap between computational fluid dynamics and vascular biology and intends to produce a quantified reference database of endothelial expression of key vascular factors in response to differential levels of hemodynamic stress. The output of this proposal can then be applied to future CFD simulations of aneurysms and permit an informed estimate of the endothelial response to a given level of hemodynamic stress. Dr. Levitt believes these findings will link computer simulations with actual endothelial cell activity, which will allow clinicians to better predict aneurysm risk, and develop new treatments such as gene therapy and targeted drugs to treat cerebral aneurysms without surgery.
Source: Michel R. Levitt, MD, University of Washington. This research summary has been adapted and edited from Dr. Levitt’s research proposal.
Research Study: Mechanisms of Neurocognitive Decline After Subarachnoid Hemorrhage
Primary Investigator: David Y. Chung, M.D., Ph.D., Instructor in Neurology at Harvard Medical School, Division of Neurocritical Care and Emergency Neurology at Massachusetts General Hospital
Background: Subarachnoid hemorrhage (SAH) from a ruptured brain aneurysm is a life-altering condition that affects more than 30,000 Americans and costs $5.6 billion annually. Approximately 20% of patients who survive the initial rupture will go on to have subsequent, secondary brain injury. Furthermore, even patients with relatively good outcomes frequently suffer from persistent cognitive deficits precluding return to work. Both the pathophysiology underlying secondary brain injury and the mechanisms underlying lasting cognitive deficits remain unknown.
Emerging human evidence suggests that cognitive deficits following SAH are associated with altered functional brain connectivity. Moreover, there is strong human evidence that spreading depolarizations (SD)—similar to the phenomenon of spreading depression in migraine aura—are associated with secondary injury and cognitive decline after
SAH7-13. SDs are thought to arise out of ischemia14, but it is difficult to distinguish the individual contributions of SDs and ischemia to outcome using existing animal models. Therefore, we will use novel mouse models of SAH to examine the contribution of SDs in the absence of ischemia on functional brain connectivity and neurocognitive decline.
Research Objective: The goal of Dr. Chung's research is to prevent further brain damage after aneurysm rupture and to develop therapies that help survivors recover back to their baseline function. In particular, he is trying to understand why some patients who look well after surgical repair of an aneurysm go on to develop a poorly understood syndrome of progressive brain injury and functional decline. At the same time, he is trying to understand why others who do well after their hospitalization have long-lasting cognitive problems that prevent return to work.
Dr. Chung believes that a phenomenon called spreading depolarization causes further injury after aneurysm rupture by changing how different parts of the brain connect to each other. To study spreading depolarizations and connectivity, he has developed a set of non-invasive tools to experimentally cause spreading depolarizations in an animal model of aneurysm rupture. Furthermore, he has developed ways to determine how difference parts of the brain connect to each other using a cutting edge technique in living mice called resting state optical intrinsic signal imaging.
Outcomes: With funds from The Aneurysm and AVM Foundation, Dr. Chung believes that the findings from his research will be important for understanding why survivors of aneurysm rupture continue to develop brain injury in the hospital and suffer persistent long term cognitive deficits. The greatest hope is that knowledge gained from his work will lead to a breakthrough in the field and directly lead to new therapies for people who have had a ruptured brain aneurysm.
Source: David Y. Chung, M.D., Ph.D., Massachusetts General Hospital and Harvard Medical School . This research summary has been adapted and edited from Dr. Chung's research proposal.
Research Study: Histological and Blood Flow Evaluations of AVM and Cerebral Artery Vasculature to Create a Simple Computational Fluid Dynamic Model of Arteriovenous Malformations
Primary Investigator: Nina Moore, MD, MSE, Dept. of Neurosurgery at the Cleveland Clinic Foundation
Background: Carrying a 3% risk of hemorrhage per year, cerebral arterial venous malformations (AVMs) pose a difficult question to physicians who need to decide whether to treat the AVM or monitor conservatively as was recently suggested in the ARUBA trial. With a paucity of prospective studies that stratify the risk of AVM rupture based on specific anatomic features, physicians have to piece together outcome studies that may not fir their patient’s AVM. It would be clinically useful to have the ability to accurately predict whether a patient’s particular AVM anatomy would predispose them to rupture and the timeframe in which to expect rupture.
Computational fluid dynamics (CFD) is a promising technique for modeling the human vascular system and examining vascular disease processes. Models of the cardiac anatomy and cerebral aneurysms with CFD are adding insight into the hemodynamic changes the vessels undergo. CFD models can illuminate risk factors with particular shape, sizes, and flow patterns seen in aneurysms and vascular malformations as different stresses affect the vessels. This knowledge can significantly expand when CFD is coupled with structural analysis of blood vessel walls providing a more comprehensive way to evaluate cerebrovascular disease. To date, this technique has not been applied to modeling of cerebral AVMs.
Research Objective: Utilizing the field’s current understanding of computational fluid dynamics applied to cerebral aneurysm and blood vessels, the object of this research is to develop a simple model of an AVM using properties defined by histologic analysis of cerebral blood vessel wall structure as well as resected arteriovenous malformation vessels. Additionally, the work will seek to obtain intraoperative and angiographic comparisons of velocity within the arteriovenous malformations to correctly simulate arteriovenous malformation flow physiology. Specifically, Dr. Moore hypothesizes that they can create a simple AVM model within a computational fluid dynamics program that incorporates accurate anatomical wall structure properties and accurate flow parameters. This model could then be later evaluated to predict the parameters of distension and failure of the vascular malformation wall. The long term goal of this project is to develop a personalized medical approach to a patient’s unique AVM. The hope is that the information learned from these simulations would serve as the groundwork for the development of a tool that allows for testing of different treatment strategies—embolization, surgery, radiosurgery or conservative therapy, eventually allowing the surgeon to even test details of their approach for treatment of an AVM.
Outcomes: With funding from The Aneurysm and AVM Foundation, Dr. Moore and her team will work in three phases. The first phase will be cerebrovascular wall histological studies, followed by phase two consisting of the study of blood flow rate in live AVMs, and finally phase three which will be the creation of the computational fluid dynamics model. Utilizing the date from this study, Dr. Moore hopes to progress towards building a mathematical model that accurately predicts the natural history of rupture in AVMs giving surgeons and patients a roadmap to better treatment strategies.
Source: Nina Moore, MD, MSE the Cleveland Clinic Foundation. This research summary has been adapted and edited from Dr. Moore's research proposal.
Research Study: Ceruloplasmin concentration and ferroxidase activity in CSF and risk of brain injury after aSAH
Primary Investigator: Joao Gomes, MD (PI), Assistant Professor of Medicine (Neurology), Neurointensivist and Director of the neuro-ICU at Cleveland Clinic; Leah P. Shriver, PhD (Co-I), Assistant Professor at the University of Akron in the Department of Chemistry; and Christopher J. Ziegler, PhD (Co-I, Professor at the University of Akron in the Department of Chemistry
Background: There is accumulating evidence that iron-mediated brain injury and oxidative damage contribute to poor outcomes following aneurysmal subarachnoid hemorrhage (aSAH). Because of its ferroxidase action, the protein ceruloplasmin (Cp) regulates iron levels in the central nervous system and prevents free radical injury.
Paradoxically, reactive oxygen species can bring about modifications in the structure of Cp that result in decreased ferroxidase activity, potentiating a vicious cycle of oxidative stress.
Research Objective: The objective of Drs. Ziegler, Shriver, and Gomes’ research is to examine the relationship between Cp concentration and its ferroxidase activity in cerebrospinal fluid and the development of delayed cerebral ischemia and neuronal cell injury following aSAH. Furthermore, they want to determine if CNS Cp undergoes oxidation and structural modifications following aSAH that result in decreased enzymatic activity.
This represents a novel pathway for aSAH pathogenesis and a promising potential therapeutic target that thus far remains unexplored.
Outcomes: With funding from The Aneurysm and AVM Foundation, Drs. Ziegler, Shriver and Gomes hope to showcase that Cp has a protective effect following aSAH and that its concentration and ferroxidase activity in CSF are inversely associated with the development of DCI. Furthermore, we hypothesize that the oxidative milieu present in the CSF of high grade aSAH patients will lead to modifications in the protein structure of the Cp molecule that will in turn result in decreased enzymatic activity and higher risk of DCI.
Source: Joao Gomes, MD the Cleveland Clinic. This research summary has been adapted and edited from Dr. Gomes’ research proposal.
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 of this project is to determine if SAH patients will have higher markers of platelet activation and platelet-leukocyte aggregates compared to controls,and that poor grade SAH patients will have higher markers compared to SAH 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.