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Zipfel Lab

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  • The Zipfel Cerebrovascular Lab

    Neurosurgery -- Washington University in St. Louis

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  • OUR MISSION

    To understand the mechanisms driving acute and chronic cerebrovascular diseases, identify new molecular targets, and develop novel therapies to improve the lives of our patients.

     

    We have three primary areas of interest:

    1) Understanding the mechanisms of vascular oxidative stress and their contribution to Cerebral Amyloid Angiopathy (CAA) and Alzheimer's Disease

    2) Applying conditioning-based therapy to prevent or reduce secondary brain injury and improve patient outcome after Aneurysmal Subarachnoid Hemorrhage (SAH)

    3) Establishing international multicentric consortia to study cerebrovascular disease including the Consortium for Dural Arteriovenous Fistula Outcome (CONDOR). The CONDOR database houses >1000 dural arteriovenous fistula patients with over 150 distinct variables and has published >10 papers that improve our understanding and management of this rare cerebrovascular disorder.

     

    Our laboratory is a unique and collaborative working environment embedded within a dynamic interdisciplinary research program called the Hope Center Program for Protein Aggregation and Neurodegeneration. We recently re-located (along with the vast majority of neuroscience labs at Washington University) to the new, state-of-the art Jeffrey T. Fort Neuroscience Research Building ("Fort Labs").

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  • THE PRINCIPAL INVESTIGATOR

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    Gregory J. Zipfel, MD

    Dr. Zipfel grew up in Peoria, IL, the son of two teachers. He attended college at the University of Illinois and graduated with honors from Northwestern University Medical School. After completing residency and fellowship at the University of Florida and the University of Miami, he returned to the Midwest in 2004 to begin his career as a neurosurgeon-scientist. Currently, Dr. Zipfel serves as Professor and Chair of Neurosurgery at Washington University and Neurosurgeon-in-Chief at Barnes-Jewish Hospital. He is a passionate clinician, scientist, educator, and mentor. He particularly enjoys the opportunity to care for patients with cerebrovascular disease while also performing fundamental research with the goal of translating findings back to the clinic to improve patient outcomes in the future.

  • LAB MEMBERS

    We are a collaborative and diverse group of scientists driven to making fundamental discoveries in the lab and rapidly translating these insights to the clinic.  

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    Gregory J. Zipfel, MD

    Principal Investigator

    Dr. Zipfel's lab has been continuously funded by the NIH since 2005 and currently includes two active R01's. He is a passionate mentor with a long track record of successful mentees -- a group that includes numerous neurosurgical, 1 neurology, and 1 anesthesiology faculty; 8 post-doctoral fellows; over 15 medical students; and over 20 undergraduates. He is exceedingly proud of the careers lab alumni have experienced including >95% of undergraduates going to medical school.

     

     

     

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    Deepti Diwan, PhD

    Instructor - Research Track

    Dr. Diwan received her Ph.D. in genome profiling from Saitama University in Saitama City, Japan. She joined the Zipfel lab in 2017. She focuses her research on deciphering the molecular mechanisms underlying hypoxic post-conditioning-induced neurovascular protection in subarachnoid hemorrhage.

     

     

     

     

     

     

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    Jogender Mehla, PhD

    Assistant Professor - Research Track

    Dr. Mehla completed his PhD at All India Institute of Medical Sciences and a Post-Doctoral Fellowship in the labs of Drs. Robert McDonald and Majid Mohajerani at the Canadian Centre for Behavioural Neuroscience, University of Lethbridge. Dr. Mehla joined the Zipfel lab in 2019, and his research focuses on determining the role and elucidating the mechanisms of vascular oxidative stress and cerebral amyloid angiopathy in Alzheimer's disease.

     

     

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    Jimmy Nelson, PhD

    Staff Scientist

    Jimmy is a former research technician in the Zipfel lab who completed his PhD at Baylor University. Jimmy returned as a staff scientist in the Zipfel lab in 2019. He has years of experience with a variety of experimental techniques, with special expertise in developing and advancing animal models of neurological disease.

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    Umeshkumar Athiraman, MD

    Associate Professor, Anesthesiology

    Dr. Athiraman was recruited to the Anesthesiology Department at Washington University in St. Louis in 2015 and joined the Zipfel lab soon thereafter. He directs clinical anesthesia for neurosurgery and is the Program Director for the Neuroanesthesia fellowship. His research focuses on applying anesthetic conditioning to subarachnoid hemorrhage -- as a therapeutic and as a means for discovering new druggable molecular targets.

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    Ananth K. Vellimana, MD

    Assistant Professor, Neurosurgery

    Dr. Vellimana trained at All India Institute of Medical Sciences for medical school, completed a post-doctorate in the Zipfel lab, completed his neurosurgery residency and neuroendovascular fellowship at Washington University in St. Louis, and his cerebrovascular fellowship at the University of Washington. He is now an Assistant Professor of Neurosurgery. He focuses his research on elucidating the mechanisms underlying subarachnoid hemorrhage-induced delayed cerebral ischemia and hypoxic conditioning-induced brain protection in subarachnoid hemorrhage.

     

  • Students

    Our students are involved in cutting-edge Neuroscience research and contribute to the advancement of biomedical knowledge. Students are prepared for their future goals through science writing, performing many lab procedures as well as learning animal handling and microsurgical skills.

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    Molly Dillon

    Undergraduate

    Molly is a sophomore at WashU majoring in Biology on the Neuroscience Track with a minor in Global Health and the Environment. Molly's goal is to pursue medical school after graduation.

    She joined the Zipfel Lab in August 2022 and has been an integral part of the research team focusing on Alzheimer’s Disease since then. Through her work with Dr. Mehla, Molly has learned about the pathophysiology of Dementia as well as how to perform advanced lab techniques.

     

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    Sarah Cao

    Undergraduate

    Sarah is a rising junior at Washington University majoring in Psychology, Neuroscience, and Philosophy. She plans on becoming a physician in the future with an interest in the neurological sciences. She joined the lab in February of 2024 and has been a dedicated lab member since. She’s excited to continue expanding her research expertise and to learn more about the pathology of Alzheimer’s disease.

     

     

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    Aminah Mostafa

    Undergraduate

    Aminah is currently a junior at WashU studying Biology and Psychology with the intention to pursue a career in medicine following her graduation. She joined the Zipfel Lab in June 2021 and has spent time studying under both Dr. Diwan and Dr. Mehla. Her current research focuses on the mechanistic links between cerebral amyloid angiopathy and Alzheimer’s disease.

     

     

     

     

     

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    Hannah Do

    Undergraduate

    Hannah is a sophomore at Washington University majoring in Neuroscience and Economics. She joined the lab in February of 2025. With plans to attend medical school and become a physician, she is looking forward to engaging in cerebrovascular research

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    Ryan Harrigan

    Medical Student

    Ryan is a phase 1 medical student at Washington University School of Medicine who is interested in neurosurgery. He joined the lab in January 2025. He received his BA is Neuroscience at Washington University in St. Louis and is passionate about the pathology of Alzheimer's disease and subarachnoid hemorrhages: he is excited about having the opportunity to learn novel and exciting concepts for both.

  • Alumni

    We are extremely proud of all past members of the Zipfel lab 

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    Anja Srienc

    Endovascular Fellow,

    Johns Hopkins

    Lab years: 2021-2023

    Position: Post-doc

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    Erin Walker

    Medical Student,

    NIH / South Carolina Medical School

    Lab years: 2022

    Position: Med Student

     

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    Alan Chen

    Medical Student,

    Columbia Medical School

    Lab years: 2019-2023

    Position: Undergraduate

     

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    Kevin Oloomi

    Gap Year,

    Mt. Sinai Medical School

    Lab years: 2020-2023

    Position: Undergraduate

     

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    Keshav Jayaraman

    PGY-1, Internal Medicine-Pediatrics, Indiana University

    Lab years: 2018-2022

    Position: Med Student

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    Hari S. Raman

    Fellow, Hematology-Oncology, Dana-Farber Cancer Institute, Boston, MA

    Lab years: 2017-2018

    Position: Med Student

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    Julia Suggs

    Resident PGY-5, Vascular Surgery

    Washington University in St. Louis

    Lab year: 2017

    Position: Med Student

     

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    Diane Aum

    Resident PGY-7, Neurosurgery

    Washington University in St. Louis

    Lab years: 2016-2017

    Position: Med Student

     

     

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    Ridhima Guniganti

    Resident, Ophthalmology, University of Louisville

    Lab years: 2016-2017

    Position: Med Student

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    Brent Bruck

    Physician, Ophthalmology

    Lab years: 2015-2016

    Position: Med Student

     

     

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    Molly Lawrence

    PGY-4, Neurology, University of Chicago

    Lab years: 2015-2018

    Position: Undergraduate

     

     

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    Matt Mollman

    Physician, Emergency Medicine

    St. Louis, MO

    Lab years: 2013-2014

    Position: Med Student

     

     

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    Eunjae Lee

    Resident PGY-4,

    Obstetrics-gynecology,

    Main Line Health

    Lab years: 2012-2016

    Position: Undergraduate

     

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    Chad Washington

    Associate Professor and Chair, Neurosurgery,

    University of Mississippi

    Lab years: 2012-2014

    Position: Post-doctorate

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    Glenn Harris

    Neuromuscular Fellow, Neurology,

    Northwestern University School of Medicine

    Lab years: 2012-2014

    Position: Undergraduate

     

     

     

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    Andrew Johnson

    Medical Science Liaison,

    Mallinckrodt Pharmaceuticals

    Lab years: 2012-2014

    Position: Post-doctorate

     

     

     

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    Emily Lin

    Physician, Internal Medicine, Milwaukee, WI

    Lab years: 2012-2015

    Position: Undergraduate

     

     

     

     

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    Bhuvic Patel

    Assistant Professor, Neurosurgery, Washington University in St. Louis

    Lab years: 2012-2014

    Position: Med Student

     

     

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    Matthew Reynolds

    Assistant Professor, Neurosurgery

    Loyola University

    Lab years: 2012-2014

    Position: Post-doctorate

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    James Baek

    PGY-2, Resident, Neurosurgery, University of Minnesota

    Lab years: 2012-2014

    Position: Undergraduate

     

     

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    Tej Azad

    Neurosurgery Resident PGY-6,

    Johns Hopkins University

    Lab years: 2010-2013

    Position: Undergraduate

     

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    Michael Harries

    Pediatric Emergency Medicine Fellow, Lurie Children's, Chicago, IL 

    Lab years: 2010-2013

    Position: Undergraduate 

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    Jacob Greenberg

    Assistant Professor, Neurosurgery, Washington University in St. Louis

    Lab years: 2010-2011

    Position: Med Student

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    David Kim

    Physician, Pain Management

    Lab years: 2010-2011

    Position: Med Student

     

     

     

     

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    Terry Kummer

    Associate Professor of Neurology, Washington University School of Medicine in Saint Louis

    Lab years: 2010-2015

    Position: Instructor

     

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    Meng-liang Zhou

    Associate Professor, Neurosurgery

    Nanjing University, China

    Lab years: 2008-2010

    Position: Post-doctorate

     

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    Spiros Blackburn

    Associate Professor & Residency Program Director,

    University of Texas-Houston

    Lab years: 2008-2009

    Position: Post-doctorate

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    Yan Wang

    Assistant Professor, Vascular Neurology

    Washington University in St. Louis

    Lab years: 2008

    Position: Undergraduate

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    Hyung-Jin Lee

    Professor, Neurosurgery

    Catholic University,

    South Korea

    Lab years: 2008-2009

    Position:Post-doctorate

     

     

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    Min Yoo

    Physician, PM&R

    Mayo Clinic, Scottsdale, AZ

    Lab years: 2007-2010

    Position: Undergraduate

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    Eric Milner

    Instructor,

    Arizona State University

    Lab years: 2006-2014

    Position: Grad Student

     

  • Aneurysmal Subarachnoid Hemorrhage (SAH)

    SELECTED PUBLICATIONS

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    Development and Validation of a Prechiasmatic Mouse Model of Subarachnoid Hemorrhage to Measure Long-Term Cognitive Deficits

    Advanced Sciences, 2024

    In this study, we developed a new subarachnoid hemorrhage (SAH) mouse model that develops trackable long-term neurocognitive deficits that can be used to investigate the complex pathophysiology of SAH and identify novel druggable therapeutic targets for SAH patients suffering long-term neurocognitive deficits.

    For details, click here.

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    Peripheral macrophages in the development and progression of structural cerebrovascular pathologies

    JCBFM, 2024

    The drivers of cerebrovascular diseases are extensive, yet inflammation is intimately tied to all of their progressions. Central to this inflammatory hypothesis is the role of peripheral macrophages; targeting this critical cell type may lead to diagnostic and therapeutic advancement in this area. Here, we comprehensively review the role that peripheral macrophages play in cerebrovascular pathogenesis, provide a schema through which macrophage behavior can be understood in cerebrovascular pathologies, and describe emerging diagnostic and therapeutic avenues in this area.

    For details, click here.

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    SIRT1 mediates hypoxic postconditioning- and resveratrol-induced protection against functional connectivity deficits after subarachnoid hemorrhage

    JCBFM, 2022

    In this study, we examined the impact of experimental SAH and the effectiveness of subsequent treatment on Functional Connectivity (FC) deficits. We showed that endovascular perforation SAH induces global and network-specific deficits in FC by day 3, corresponding with the time frame of DCI in mice. Hypoxic conditioning provides SIRT1-mediated protection against these network-specific FC deficits, as does treatment with the SIRT1 activator, resveratrol. Conditioning-based therapy provides multifaceted protection in experimental SAH.

    For details, click here.

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    SIRT1 mediates hypoxic preconditioning induced attenuation of neurovascular dysfunction following subarachnoid hemorrhage

    Experimental Neurology, 2020

    We used the SIRT1-specific inhibitor, EX527, and the SIRT1 activator, Resveratrol, to show that hypoxia-induced augmentation of SIRT1 is a critical molecular mediator of the robust neurovascular protection afforded by hypoxic preconditioning in experimental SAH. These results indicate SIRT1 activation is a promising, novel, pleiotropic therapeutic strategy to combat Delayed Cerebral Ischemia after SAH.

    For details, click here.

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    Role of eNOS in Isoflurane Conditioning-Induced Neurovascular Protection in Subarachnoid Hemorrhage

    JAHA, 2020

     

    We used the pan nitric oxide synthase inhibitor, L-NAME, along with genetically modified mice constitutively lacking eNOS to show that the robust protection afforded by isoflurane conditioning against SAH-induced delayed cerebral ischemia is critically mediated via isoflurane-induced augmentation in eNOS.

     

     

     

    For details, click here.

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    Microvascular platelet aggregation and thrombosis after subarachnoid hemorrhage: A review and synthesis

    JCBFM, 2020

    The focus of this review was to provide an overview of experimental animal model studies and human autopsy studies that explore the temporal- spatial characterization and mechanism of microvascular platelet aggregation and thrombosis following subarachnoid hemorrhage (SAH), as well as to critically assess experimental studies and clinical trials highlighting preventative therapeutic options against this highly morbid pathophysiological process.

    For details, click here.

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    Minocycline protects against delayed cerebral ischemia after subarachnoid hemorrhage via MMP‐9 inhibition

    Annals Clinical & Translational Neurology, 2017

    In this study, we demonstrated that MMP-9 expression and activity are increased after subarachnoid hemorrhage in mice. We also showed that genetic (knockout) and pharmacological (minocycline) inhibition of MMP-9 decreases vasospasm and neurobehavioral deficits in mice, and that minocycline administration to MMP-9 knockout mice does not yield additional protection. We also showed that minocycline reduces vasospasm in rabbits. These data indicate MMP-9 is a key player in the pathogenesis of subarachnoid hemorrhage-induced delayed cerebral ischemia, and that minocycline has promise as a novel MMP-9 directed therapy for subarachnoid hemorrhage patients.

    For details, click here.

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    A novel fluorescent imaging technique for assessment of cerebral vasospasm after experimental subarachnoid hemorrhage

    Scientific Reports, 2017

    We applied ROX SE fluorescent imaging to our mouse model of subarachnoid hemorrhage and found that this novel imaging technique is qualitatively and quantitatively superior to India ink-gelatin casting for the assessment of cerebral vasospasm, while also permitting outstanding immunohistochemical examination of non-vasospasm components of secondary brain injury.

    For details, click here.

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    A Phase I proof-of-concept and safety trial of sildenafil to treat cerebral vasospasm following subarachnoid hemorrhage

    Journal of Neurosurgery, 2016

    In this study, subarachnoid hemorrhage patients with angiographically confirmed vasospasm were treated with intravenous silenafil and monitored for safety and efficacy. Of the 12 treated patients, 8 (67%) had a positive angiographic response, 3 (60%) in the low-dose group and 5 (71%) in the high-dose group. The largest degree of vessel dilation was an average of 0.8 mm (range 0-2.1 mm). This corresponded to an average percentage increase in vessel diameter of 62% (range 0%-200%). Results from this Phase I clinical trial showed sildenafil is safe and well tolerated in the setting of subarachnoid hemorrhage and suggest a positive impact on vasospasm.

    For details, click here.

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    HIF-1α Mediates Isoflurane-Induced Vascular Protection in Subarachnoid Hemorrhage

    Annals Clinical & Translational Neurology, 2015

     
    In this study, we showed that isoflurane postconditioning reduced cerebral vasospasm, microvessel thrombosis, microvascular dysfunction, and neurological deficits in wild-type mice. Isoflurane-induced protection against subarachnoid hemorrhage-induced delayed cerebral ischemia was attenuated in 2ME2-treated wild-type mice and endothelial cell-specific HIF-1α-null mice. These results implicate cerebral vessels as a key target for the brain protection afforded by isoflurane postconditioning, and HIF-1α as a critical mediator of this vascular protection. They also identify isoflurane postconditioning as a promising novel therapeutic for subarachnoid hemorrhage.

     

    For details, click here.

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    eNOS Mediates Endogenous Protection Against Subarachnoid Hemorrhage-induced Cerebral Vasospasm

    Stroke, 2011

    In this study, we showed that hypoxic preconditioning (PC) nearly completely prevented subarachnoid hemorrhage-induced reduction in nitric oxidate availability, vasospasm and neurological deficits. This protection was lost in wild-type mice treated with the nitric oxide synthase inhibitor, L-NAME, and in eNOS-null mice. These data indicate endogenous protective mechanisms against vasospasm exist, are powerful, can be induced by PC, and are critically dependent on eNOS-derived nitric oxide. They also suggest conditioning-based therapy is a promising new strategy to reduce vasospasm and delayed cerebral ischemia after subarachnoid hemorrhage.

    For details, click here.

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    Amyloid-β Dynamics Correlate with Neurological Status in the Injured Human Brain

    Science, 2008

    In this study, we used intracerebral microdialysis to obtain serial brain interstitial fluid samples in patients undergoing invasive intracranial monitoring after acute brain injury. We found a strong positive correlation between changes in brain interstitial fluid Aβ concentrations and neurological status. We also found that brain interstitial fluid Aβ concentrations were lower when other cerebral physiological and metabolic abnormalities reflected depressed neuronal function. Such dynamics fit well with the hypothesis that neuronal activity regulates extracellular Aβ concentrations.

    For details, click here.

  • Dementia

    SELECTED PUBLICATIONS

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    STAT3 inhibitor mitigates cerebral amyloid angiopathy and parenchymal amyloid plaques while improving cognitive functions and brain networks

      Acta Neuropathologica Communications, 2021

      In this study, the impact of STAT3 inhibition on cognition, cerebrovascular function, amyloid pathology, oxidative stress, and neuroinflammation was studied using in vitro and in vivo models of Alzheimer’s disease (AD)-related pathology. Our results demonstrated functional improvements associated with a reduction in neuritic plaques, cerebral amyloid angiopathy (CAA), oxidative stress, and neuroinflammation. Reduction in amyloid precursor protein (APP) processing and attenuation of oxidative modification of lipoprotein receptor related protein-1 (LRP-1) were identified as potential underlying mechanisms. These results demonstrate the broad impact of STAT3 on cognitive functions, parenchymal and vascular amyloid pathology and highlight the therapeutic potential of STAT3 specific inhibition for treatment of AD and CAA.

      For details, click here.

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      APOE immunotherapy reduces cerebral amyloid angiopathy and amyloid plaques while improving cerebrovascular function

      Science Translational Medicine, 2021

      In this study, we investigated the potential therapeutic effects of the anti-human APOE antibody HAE-4, which selectively recognizes human APOE that is co-deposited with Aβ in cerebral amyloid angiopathy (CAA) and parenchymal amyloid pathology. In chronically treated 5XE4 mice, HAE-4 reduced Aβ deposition including CAA compared to a control antibody, whereas the anti–Aβ antibody had no effect on CAA. Furthermore, the anti–Aβ antibody exacerbated microhemorrhage severity, which highly correlated with reactive astrocytes surrounding CAA. In contrast, HAE-4 did not stimulate microhemorrhages and instead rescued CAA-induced cerebrovascular dysfunction in leptomeningeal arteries in vivo. HAE-4 not only reduced amyloid but also dampened reactive microglial, astrocytic, and proinflammatory-associated genes in the cortex. These results suggest that targeting APOE in the core of both CAA and plaques could ameliorate amyloid pathology while protecting cerebrovascular integrity and function.

      For details, click here.

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      Passive immunotherapy targeting amyloid-β reduces cerebral amyloid angiopathy and improves vascular reactivity

      Brain, 2016

       

      In this study, we showed that hronic administration of the anti-Aβ40 specific antibody, ponezumab, reduced Aβ accumulation both in leptomeningeal and brain vessels in aged Tg2576 mice. Acute administration of ponezumab triggered a significant and transient increase in interstitial fluid Aβ40 levels in aged Tg2576 mice. A beneficial effect on vascular reactivity following acute administration of ponezumab was also noted, even in vessels where there was severe CAA. These data favor a mechanism that involves rapid removal and/or neutralization of Aβ species that may otherwise be detrimental to normal vessel function.

       

       

      For details, click here.

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      Heparan sulfate proteoglycans (HSPG) mediate Aβ-induced oxidative stress and hypercontractility in cultured vascular smooth muscle cells (VSMC)

      Molecular Neurodegeneration, 2016

       

       

      In this study, we demonstrated that pharmacological depletion of HSPG in cultured VSMC mitigates Aβ40- and Aβ42-induced oxidative stress. We also found that Aβ40 (but not Aβ42) causes a hypercontractile phenotype in cultured VSMC that likely results from a HSPG-mediated augmentation in intracellular Ca(2+) activity. Taken together, our data indicate that HSPG are critical mediators of Aβ-induced oxidative stress and Aβ40-induced VSMC dysfunction, and suggests HSPG may play a critical core in CAA-induced cerebrovascular dysfunction and CAA pathogenesis. 

       

      For details, click here.

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      Contribution of reactive oxygen species to cerebral amyloid angiopathy, vasomotor dysfunction, and microhemorrhage in aged Tg2576 mice

      PNAS, 2015

       

      In this study, we showed that the NADPH oxidase inhibitor, apocynin (Apo), and the free radical scavenger, tempol, reduce oxidative stress and improve vessel reactivity in aged Tg2576 mice; the improved cerebrovascular function is due to reduction in CAA formation and a decrease in CAA-induced vasomotor impairment; and antioxidant therapies attenuate CAA-related microhemorrhage. These results indicate oxidative stress is a key contributor to CAA formation, CAA-induced vessel dysfunction, and CAA-related microhemorrhage, and suggest that NADPH oxidase-derived oxidative stress is a promising therapeutic target for patients with CAA and Alzheimer's disease.

      For details, click here.

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      Cerebral amyloid angiopathy (CAA) increases susceptibility to infarction after focal cerebral ischemia in Tg2576 mice

      Stroke, 2014

      In this study, we demonstrated that aged Tg2576 mice have more severe cerebrovascular dysfunction that is CAA dependent, have greater cerebral blood flow compromise during and immediately after middle cerebral artery occlusion, and develop larger infarctions after middle cerebral artery occlusion. These data indicate CAA induces a more severe form of cerebrovascular dysfunction than soluble Aβ alone, leading to intra- and postischemic cerebral blood flow deficits that ultimately exacerbate cerebral infarction.

      For details, click here.

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      Resorufin analogs preferentially bind cerebrovascular amyloid: potential use as imaging ligands for cerebral amyloid angiopathy

      Molecular Neurodegeneration, 2011

      In this study, we demonstrated that the phenoxazine derivative, resorufin, preferentially binds CAA (arrowheads) over neuritic plaques (arrows) in aged Tg2576 mice. We also found that resorufin staining was predominantly noted in amyloid-laden vessels in postmortem Alzheimer's brain tissues, and that resorufin selectively visualizes CAA in live Tg2576 mice when topically administered. Resorufin analogs are the fist class of amyloid dye that discriminate between cerebrovascular and neuritic forms of amyloid. This binding selectivity suggests resorufin analogs have great potential as a CAA-specific amyloid tracer that could permit non-invasive detection and quantification of CAA in live patients.

      For details, click here.

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      Cerebrovascular dysfunction in amyloid precursor protein transgenic mice: contribution of soluble and insoluble amyloid-beta peptide, partial restoration via gamma-secretase inhibition

      Journal of Neuroscience, 2008

      In this study, we showed that a strong correlation between CAA severity and vessel reactivity exists in Tg2576 mice; a surprisingly small amount of CAA produces marked reduction or complete loss of vessel function; CAA-induced vasomotor impairment results from dysfunction rather than loss or disruption of vascular smooth muscle cells; and acute depletion of Aβ improves vessel function in young and to a lesser degree aged Tg2576 mice. These results suggest soluble and insoluble Aβ causes vasomotor impairment, that mechanisms other than Aβ-induced alteration in vessel integrity are responsible, and that anti-Aβ therapy may have beneficial effects on vascular as well as parenchymal amyloid.

      For details, click here.

    • Consortium for dAVF Outcome Research (CONDOR)

      SELECTED PUBLICATIONS

      Dural Arteriovenous Fistulas With Cognitive Impairment: Angiographic Characteristics and Treatment Outcomes

      Neurosurgery, 2023

       

      We conducted an analysis of the largest cohort of dAVFs presenting with cognitive impairment (dAVFs-CI), aiming to provide a detailed characterization of this subset of dAVFs. A total of 60 patients with dAVFs-CI and 60 control dAVFs were included. Outflow obstruction leading to venous hypertension was observed in all dAVFs-CI. Sinus stenosis was significantly associated with dAVFs-CI (OR 2.85, 95% CI: 1.16-7.55, P = .027). dAVFs-CI were more likely to have a higher number of arterial feeders (OR 1.56, 95% CI 1.22-2.05, P < .001) and draining veins (OR 2.05, 95% CI 1.05-4.46, P = .004). Venous ectasia increased the risk of dAVFs-CI (OR 2.38, 95% CI 1.13-5.11, P = .024). Overall, we found that venous hypertension is a key angiographic feature of dAVFs-CI. The presence of venous ectasia further exacerbates the impaired drainage and contributes to the development of dAVFs-CI. Notably, in certain cases, closure of the dAVF has the potential to reverse symptoms.

       

       

       

       

       

       

       

      For details, click here.

      Natural history, angiographic presentation and outcomes of anterior cranial fossa dural arteriovenous fistulas

      Journal of Neurointerventional Surgery, 2023

       

      Anterior cranial fossa (ACF)-dAVFs were selected from the cohort of 1077 arteriovenous fistulas in CONDOR. The most common symptomatic presentation was intracranial hemorrhage (22/38, 57%). Most ACF-dAVFs drained through cortical veins (85%, 51/60), which in most instances drained into the superior sagittal sinus (63%, 32/51). The presence of cortical venous drainage predicted symptomatic presentation (OR 9.4, CI 1.98 to 69.1, p=0.01). Microsurgery was the most effective modality of treatment. 56% (19/34) of symptomatic patients who were treated had complete resolution of symptoms. Improvement of symptoms was not observed in untreated symptomatic ACF-dAVFs. Overall, we found that most ACF-dAVFs have a symptomatic presentation. Drainage through cortical veins is a key angiographic feature of ACF-dAVFs that accounts for their malignant course. Microsurgery is the most effective treatment. Due to the high risk of bleeding, closure of ACF-dAVFs is indicated regardless of presentation.

       

      For details, click here.

      Risk of Early Versus Later Rebleeding From Dural Arteriovenous Fistulas With Cortical Venous Drainage

      Stroke, 2022

       
      Patients with dural arteriovenous fistula and cortical venous drainage presenting with hemorrhage were identified from the multinational CONDOR. Of 1077 patients, 250 met the inclusion criteria and had 95 cumulative person-years natural history follow-up. The overall annualized rebleed rate was 7.3% (95% CI, 3.2-14.5). The incidence rate of rebleeding in the first 2 weeks was 0.0011 per person-day; an early rebleed risk of 1.6% in the first 14 days (95% CI, 0.3-5.1). For the remainder of the first year, the incidence rate was 0.00015 per person-day; a rebleed rate of 5.3% (CI, 1.7-12.4) over 1 year. The incidence rate ratio was 7.3 (95% CI, 1.4-37.7; P, 0.026). Overall, we found that the risk of rebleeding of a dural arteriovenous fistula with cortical venous drainage presenting with hemorrhage is increased in the first 2 weeks justifying early treatment. However, the magnitude of this increase may be considerably lower than previously thought. Treatment within 5 days was associated with a low rate of rebleeding and appears an appropriate timeframe.

       

      For details, click here.

      Outcome Following Hemorrhage From Cranial Dural Arteriovenous Fistulae - Analysis of the Multicenter International CONDOR Registry

      Stroke, 2021

       

      CONDOR yielded 262 patients with incident hemorrhage, with median follow-up of 1.4 years. Poor outcome was observed in 17.0% (95% CI, 12.3%–21.7%), including a 3.6% (95% CI, 1.3%–6.0%) mortality. Age and anticoagulant use were associated with poor outcome on multivariable analysis (odds ratio, 1.04, odds ratio, 5.1 respectively). Subtype of hemorrhage and venous shunting pattern of the lesion did not affect outcome significantly. Within the CONDOR registry, dural arteriovenous fistula–related hemorrhage was associated with a relatively lower morbidity and mortality than published outcomes from other arterialized cerebrovascular lesions but still at clinically consequential rates.

       

       

       

       

       

       

       

       

       

       

      For details, click here.

      Consortium for Dural Arteriovenous Fistula Outcomes Research (CONDOR): rationale, design, and initial characterization of patient cohort

      Journal of Neurosurgery, 2021

       

      CONDOR comprises 14 centers in the United States, the United Kingdom, the Netherlands, and Japan that have pooled their data from 1077 dAVF patients seen between 1990 and 2017. Overall, 852 patients (79%) presented with fistula-related symptoms: 427 (40%) presented with nonaggressive symptoms such as tinnitus or orbital phenomena, 258 (24%) presented with intracranial hemorrhage, and 167 (16%) presented with nonhemorrhagic neurological deficits. A smaller proportion (224 patients, 21%) were asymptomatic. Many patients (85%, 911/1077) underwent treatment via endovascular embolization (55%, 587/1077), surgery (10%, 103/1077), radiosurgery (3%, 36/1077), or multimodal therapy (17%, 184/1077). The overall angiographic cure rate was 83% (758/911 treated), and treatment-related permanent neurological morbidity was 2% (27/1467 total procedures). With more than 1000 patients, the CONDOR registry represents the largest registry of cranial dAVF patient data in the world. These unique, well-annotated data will enable multiple future analyses to be performed to better understand dAVFs and their management.

       

      For details, click here.

    • EXPERIMENTAL TECHNIQUES

      We use a complementary set of molecular, cellular, genetic, and neurobehavioral approaches for our studies

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      Mouse models of amyloidosis

      Aged Tg2576, PSAPP, and 5xFAD:APOE4 transgenic mice are used to study CAA (arrows) and neuritic plaques (arrowheads) that are imaged with congo red derivative dyes like X34.

       

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      Mouse model of subarachnoid hemorrhage

      Endovascular perforation of the left internal carotid artery bifurcation (arrow) produces experimental subarachnoid hemorrhage in mice and rats.

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      Cerebral Vasospasm

      Subarachnoid hemorrhage-induce cerebral vasospasm is quantified via India ink-gelatin casting (circles) or ROX SE fluorescent imaging.

       

       

      Cerebrovascular Function

      Pial arteriole vasoreactivity to hypercapnia and topical vasoactive agents is assessed via open cranial window technique in live mice.

       

       

       

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      Functional Connectivity by Optical Imaging

      Diffuse optical tomography (DOT) is used to examine Functional Connectivity of brain networks after acute and chronic brain injury

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      Neurobehavior

      Complementary set of neurobehavioral tests are utilized including Novel Object Recognition, Novel Object Location, Y-maze, Burrowing Behavior, and Morris Water Maze.

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      Smooth Muscle Cell Contractility

      Contractility of cultured human-derived vascular smooth muscle cells is assessed via area measurements of cells (inset) following exposure to KCl and/or Abeta.

    • SOCIAL EVENTS

      Celebration Lunch for recieving a new NIH R01 Grant! Congratulations Team Zipfel!

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      Isabella, Dr. Zipfel, Anja, Jimmy, Prakash, Ahmed, Ernie, Alan, and Bao (clockwise from bottom left)

      Celebrating arrival of senior scientist, Jimmy Nelson, PhD. Welcome back Jimmy!

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      Jogender, Deepti, Matt, Jane, Umesh, Greg, Ernie, Jimmy, Keshav, and Meizi (clockwise from bottom left)

    • News

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      Inside the Zipfel Lab

      A brief tour of the Zipfel lab in the state-of-the-art Jeffrey T. Fort Neuroscience Research Building at WashU Medicine.

      March 10, 2025

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      Zipfel receives Dacey award for cerebrovascular research

      Gregory J. Zipfel, MD, head of the Department of Neurosurgery at Washington University School of Medicine in St. Louis, has been awarded the Ralph G. Dacey Jr., MD, Medal for Outstanding Cerebrovascular Research. The honor, from the Joint Cerebrovascular Section of the American Association of Neurological Surgeons and the Congress of Neurological Surgeons, recognizes surgeons whose novel research has elevated the understanding of cerebrovascular disease.
       

      January 11, 2024

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      Dr. Greg Zipfel, Receives the 2022 Drake Lecture Award

      Congratulations to Dr. Zipfel on the Drake Lectureship and for phenomenal guidance on how to approach the stages of one's career arc!

       

       

       

      October 10, 2022

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      Fort Provides Gift for Neurosurgery Innovation Fund, Professorship

      Jeffrey Fort’s gift for the Department of Neurosurgery will help Gregory Zipfel, MD, and Joshua Osbun, MD, investigate ways to improve outcomes for patients with neurological conditions, including blood vessel malformations, aneurysm, and stroke.

       

      August 03, 2020

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      Zipfel installed as Dacey Distinguished Professor of Neurological Surgery

      Professorship honors former neurosurgery head, Ralph G. Dacey, Jr. MD, who led the department of neurosurgery at Washington University in St. Louis for 30 years.

       

      December 11, 2019

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      Zipfel named Head of Neurosurgery

      “It is truly an honor to succeed my mentor and close friend as the new head of neurosurgery,” Zipfel said. “Dr. Dacey has built a world-class department over a 30-year career here at Washington University, and I see a tremendous opportunity to build upon this extraordinary foundation. I look forward to partnering with so many outstanding colleagues from the School of Medicine, Siteman Cancer Center, Hope Center, Barnes-Jewish Hospital, St. Louis Children’s Hospital and BJC. Through these partnerships, I am confident that we will reach our overarching goal to make a difference in patients’ lives today, while also advancing our field so we can make an even greater difference in patients’ lives tomorrow.”

      April 25, 2019

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      Med student receives fellowship to study brain damage​

      Medical student, Vivian Lee, receives the Carolyn L. Kuckein Student Research Fellowship Award from the Alpha Omega Alpha National Honor Medical Society to support her research in the Zipfel lab

      August 7, 2018

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      How Krysta Owings overcame a stroke at age 25

      St. Louis Magazine highlights the care of a young woman who Dr. Zipfel treated for a ruptured brain AVM.

       

      June 6, 2018

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      St. Louis woman says her mother saved her life after stroke

      St. Louis NBC affiliate, KSDK, highlights the care of a 25 year old woman who Dr. Zipfel treated for a ruptured brain AVM

      May 11, 2018

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      Washington People: Gregory Zipfel

      Neurosurgeon dedicated to making surgeries smaller, less invasive

       

       

      June 20, 2016

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      Dr. Greg Zipfel, Neurosurgeon

      Barnes-Jewish Hospital blog highlighting Dr. Zipfel's use of minimally invasive surgical approaches

      February 6, 2012

    • INTERESTED IN JOINING OUR TEAM?

      Please submit a CV and a brief description of your research background and career goals to Gregory J. Zipfel (zipfelg@wustl.edu).

      Post-Doctoral Fellow

      We are recruiting a highly motivated Post-Doctoral Research Fellow to the laboratory.
       
      This position will focus on the lab’s R01-funded research program investigating the role and mechanisms of vascular oxidative stress on Alzheimer’s Disease, Cerebral Amyloid Angiopathy, and other forms of dementia. Previous experience in vascular cell culture, vascular biology, animal models of Alzheimer's disease and other neurodegenerative conditions, animal surgery, and advanced ex vivo and in vivo imaging is strongly desired.

      Medical Students

      We are actively recruiting highly motivated Medical Students to the laboratory.

       

      Medical students typically enter the lab as a summer research student, many of which ultimately pursue a dedicated research year in the lab. To date, we have mentored 13 medical students -- all of whom have been accepted or are currently applying to highly competitive specialties including neurosurgery.

       

       

       

      Undergraduates

      We are actively recruiting highly motivated Undergraduate Students to the laboratory.
       
      Undergraduate students typically enter the lab in the first or second year of their studies and make a multi-year commitment to the lab. To date, the Zipfel Lab has mentored 11 undergraduate students -- all of whom have been accepted or are currently applying to medical school.
       
       
    • SUPPORT OUR RESEARCH

      We cannot do it alone...

      If you would like to help us in our quest to develop new treatments for our patients with Brain Aneurysms, Alzheimer's Disease, and Vascular Dementia, please contact:

       

      Laura Caveny

      University Advancement

      314-286-0450
      caveny@wustl.edu

       

    • SPECIAL THANKS

      We are indebted to our patients, benefactors, and funding sources that make our work possible.

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      Harrington / Zhou Research Fund

    • Connect With Us

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      Contact
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