Zipfel Lab

Study of pathophysiology of aneurysmal subarachnoid hemorrhage and vascular contributors to dementia.

Zipfel Lab
View Content


Vascular Contributors to Dementia/
Cerebral Amyloid Angiopathy

Cerebral amyloid angiopathy (CAA) is characterized by deposition of amyloid-β (Aβ) peptide within the walls of cerebral vessels. CAA has long been connected to cerebral hemorrhage and, more recently, has been placed as a substantial risk factor for ischemic brain injury and progressive cognitive impairment in Alzheimer’s disease. Using genetically manipulated mice that overexpress human Aβ and an in vivo cranial window preparation with fluorescent and video microscopy, we have found that both soluble and fibrillar forms of Aβ directly influence cerebrovascular function. Moreover, certain Aβ-mediated cerebrovascular effects appear reversible, as acute administration of γ-secretase inhibitors was observed to reduce soluble Aβ-mediated vascular dysfunction. Our past work shows CAA causes severe, dose-dependent cerebrovascular vasomotor impairment. CAA-induced cerebrovascular vasomotor impairment increases susceptibility to ischemic brain injury after stroke. We also found that NADPH oxidase-derived reactive oxygen species play a causal role in the cerebrovascular vasomotor impairment caused by the CAA. We found that inhibition of NADPH oxidase dramatically (by 80%) reduces the CAA formation in aged APP mice. We are currently extending these observations by examining the roles of NADPH oxidases and heparan sulfate proteoglycans as a cell surface initiator of Aβ-induced NADPH oxidase activation, vascular oxidative stress, and vascular smooth muscle cell dysfunction. We hypothesized Apolipoprotein E (ApoE) as a potential downstream effector through which NADPH oxidase-derived reactive oxygen species contribute to CAA formation. Through these studies, we hope to define the molecular underpinnings of CAA-induced cerebrovascular dysfunction and ultimately develop new strategies toward which the ischemic and cognitive effects of CAA can be prevented and/or reduced.

Aneurysmal Subarachnoid Hemorrhage

Aneurysmal subarachnoid hemorrhage (SAH), caused by rupture of an intracranial aneurysm and extravasation of blood into the subarachnoid space, is associated with high morbidity and mortality. The devastating outcomes after SAH result primarily from secondary brain injury due to two processes – early brain injury and delayed cerebral ischemia. Multiple lab projects examine the pathophysiology underlying secondary brain injury after SAH. Our prior work demonstrated that “preconditioning” with hypoxia affords strong protection against post-SAH neurovascular dysfunction. Ongoing studies extend these observations to examine the molecular pathways underlying vascular and neuronal protection afforded by “preconditioning” and “postconditioning” approaches, and also assess the translational potential of a conditioning-based strategy to combat SAH-induced neurovascular dysfunction. Other areas of interest include determining the role of matrix metalloproteinase-9 and ATP-dependent potassium channels in early brain injury, vascular dysfunction and neuronal death after SAH. The overarching purpose of this work is to identify new molecular targets with therapeutic potential in preventing or reducing the devastating consequences of aneurysm rupture.

Dural Arteriovenous Fistulae

Dural arteriovenous fistulae (dAVF) are pathologic shunts between dural arteries and dural venous sinuses and leptomeningeal veins that make up 10%-15% of all intracranial vascular malformations. Because of the relative rarity of these malformations, few centers have an adequate number of patients to perform complex analyses of natural history or treatment. Dr Zipfel has collaborated with leading investigators in the field of dAVF research to form the consortium for dural arteriovenous fistula outcomes research (CONDOR), a collaboration with a pooled data registry of almost 2000 patients. This represents the largest data registry of dAVF patients in the world and will enable multiple future analyses to improve dAVF patient outcomes.



Principal Investigator:

Gregory J. Zipfel, MD

Itender Singh, PhD 
Umeshkumar Athiraman, MD 

Research Fellows/Scientists:
Ananth Vellimana, MD

Graduate Students:
Diane J. Aum, BS
Ridhima R. Guniganti, BA
Hari Raman, BS

Research Staff:
Aluet Borrego Alvarez, MSc
Ernesto (Ernie) Gonzales, GN

Undergraduate Students:
Molly Lawrence
Devin Patel

David Brody, MD, PhD  
John Cirrito, PhD 
Jeff Gidday, PhD  
David M. Holtzman, MD  
Jin-Moo Lee, MD, PhD  
David S. Warner, MD

Consortium for Dural Arteriovenous Fistula Outcomes Research (CONDOR) collaborators: 
Michael T. Lawton, MD

Louis J. Kim, MD 
Sepideh Amin-Hanjani, MD 
Giuseppe Lanzino, MD 
Jason Sheehan, MD, PhD 
W. Christopher Fox, MD 
Rose Du, MD, PhD 
Henry Woo, MD 
J. Marc C. van Dijk, MD, MSc
Junichiro Satomi, MD  
Diederik Bulters, MBChB 
Robert M. Starke, MD 
Bradley Gross, MD 
Minako Hayakawa, MD, PhD 
Akash P. Kansagra, MD


Lab Research

Vascular Contributors to Dementia

Diagnostic and Prognostic Utility of the Synaptic Marker Neurogranin in Alzheimer Disease.

Tarawneh R, D’Angelo G, Crimmins D, Herries E, Griest T, Fagan AM, Zipfel GJ, Ladenson JH, Morris JC, Holtzman DM.
JAMA Neurology. 2016 May 1;73(5):561-71. doi: 10.1001/jamaneurol.2016.0086.

Passive immunotherapy targeting amyloid-β reduces cerebral amyloid angiopathy and improves vascular reactivity.
Bales KR, O’Neill SM, Pozdnyakov N, Pan F, Caouette D, Pi Y, Wood KM, Volfson D, Cirrito JR, Han BH, Johnson AW, Zipfel GJ, Samad TA.
Brain. 2016 Feb;139(Pt 2):563-77. doi: 10.1093/brain/awv313.

Heparan sulfate proteoglycans mediate Aβ-induced oxidative stress and hypercontractility in cultured vascular smooth muscle cells.
Reynolds MR, Singh I, Azad TD, Holmes BB, Verghese PB, Dietrich HH, Diamond M, Bu G, Han BH, Zipfel GJ.
Molecular Neurodegeneration.
 2016 Jan 22;11:9. doi: 10.1186/s13024-016-0073-8.

Contribution of reactive oxygen species to cerebral amyloid angiopathy, vasomotor dysfunction, and microhemorrhage in aged Tg2576 mice.
Han BH, Zhou ML, Johnson AW, Singh I, Liao F, Vellimana AK, Nelson JW, Milner E, Cirrito JR, Basak J, Yoo M, Dietrich HH, Holtzman DM, Zipfel GJ.
Proceedings of the National Academy of Science. 2015 Feb 24;112(8):E881-90. doi: 10.1073/pnas.1414930112.

Cerebral amyloid angiopathy increases susceptibility to infarction after focal cerebral ischemia in Tg2576 mice.
Milner E, Zhou ML, Johnson AW, Vellimana AK, Greenberg JK, Holtzman DM, Han BH, Zipfel GJ.
Stroke. 2014 Oct;45(10):3064-9. doi: 10.1161/STROKEAHA.114.006078.

Tau elevations in the brain extracellular space correlate with reduced amyloid-β levels and predict adverse clinical outcomes after severe traumatic brain injury.
Magnoni S, Esparza TJ, Conte V, Carbonara M, Carrabba G, Holtzman DM, Zipfel GJ, Stocchetti N, Brody DL.
Brain. 2012 Apr;135(Pt 4):1268-80. doi: 10.1093/brain/awr286.

Resorufin analogs preferentially bind cerebrovascular amyloid: potential use as imaging ligands for cerebral amyloid angiopathy.
Han BH, Zhou ML, Vellimana AK, Milner E, Kim DH, Greenberg JK, Chu W, Mach RH, Zipfel GJ.
Molecular Neurodegeneration. 2011 Dec 22;6:86. doi: 10.1186/1750-1326-6-86.

Soluble amyloid-beta, effect on cerebral arteriolar regulation and vascular cells.
Dietrich HH, Xiang C, Han BH, Zipfel GJ, Holtzman DM.
Molecular Neurodegeneration. 2010 Apr 13;5:15. doi: 10.1186/1750-1326-5-15.

Cerebral amyloid angiopathy: progressive disruption of the neurovascular unit.
Zipfel GJ, Han H, Ford AL, Lee JM.
Stroke. 2009 Mar;40(3 Suppl):S16-9. doi: 10.1161/STROKEAHA.108.533174.

Cerebrovascular dysfunction in amyloid precursor protein transgenic mice: contribution of soluble and insoluble amyloid-beta peptide, partial restoration via gamma-secretase inhibition.
Han BH, Zhou ML, Abousaleh F, Brendza RP, Dietrich HH, Koenigsknecht-Talboo J, Cirrito JR, Milner E, Holtzman DM, Zipfel GJ.
Journal of Neuroscience. 2008 Dec 10;28(50):13542-50. doi: 10.1523/JNEUROSCI.4686-08.2008.
Amyloid-beta dynamics correlate with neurological status in the injured human brain.
Brody DL, Magnoni S, Schwetye KE, Spinner ML, Esparza TJ, Stocchetti N, Zipfel GJ, Holtzman DM.
Science. 2008 Aug 29;321(5893):1221-4. doi: 10.1126/science.1161591.

Aneurysmal Subarachnoid Hemorrhage/Brain Injury

Experimental subarachnoid haemorrhage results in multifocal axonal injury.
Kummer TT, Magnoni S, MacDonald CL, Dikranian K, Milner E, Sorrell J, Conte V, Benetatos JJ, Zipfel GJ, Brody DL.
Brain. 2015 Sep;138(Pt 9):2608-18. doi: 10.1093/brain/awv180.

HIF-1α Mediates Isoflurane-Induced Vascular Protection in Subarachnoid Hemorrhage.
Milner E, Johnson AW, Nelson JW, Harries MD, Gidday JM, Han BH, Zipfel GJ.
Annals of Clinicial & Translational Neurology. 2015 Apr;2(4):325-37. doi: 10.1002/acn3.170.

Endovascular perforation subarachnoid hemorrhage fails to cause Morris water maze deficits in the mouse.
Milner E, Holtzman JC, Friess S, Hartman RE, Brody DL, Han BH, Zipfel GJ.
Journal of Cerebral Blood Flow and Metabolism. 2014 Sep;34(9). doi: 10.1038/jcbfm.2014.108.

Phosphodiesterase 5 inhibition attenuates cerebral vasospasm and improves functional recovery after experimental subarachnoid hemorrhage.

Han BH, Vellimana AK, Zhou ML, Milner E, Zipfel GJ.
Neurosurgery. 2012 Jan;70(1):178-86; discussion 186-7. doi: 10.1227/NEU.0b013e31822ec2b0.

Endothelial nitric oxide synthase mediates endogenous protection against subarachnoid hemorrhage-induced cerebral vasospasm.
Vellimana AK, Milner E, Azad TD, Harries MD, Zhou ML, Gidday JM, Han BH, Zipfel GJ.
Stroke. 2011 Mar;42(3):776-82. doi: 10.1161/STROKEAHA.110.607200.

Zinc translocation accelerates infarction after mild transient focal ischemia.
Lee JM, Zipfel GJ, Park KH, He YY, Hsu CY, Choi DW.
Neuroscience. 2002;115(3):871-8.

Reducing calcium overload in the ischemic brain.
Zipfel GJ, Lee JM, Choi DW.
New England Journal of Medicine. 1999 Nov 11;341(20):1543-4. Review.

The changing landscape of ischaemic brain injury mechanisms.
Lee JM, Zipfel GJ, Choi DW.
Nature. 1999 Jun 24;399(6738 Suppl):A7-14. Review.

Clinical Research

Aneurysmal Subarachnoid Hemorrhage

Predictors of 30-day readmission after aneurysmal subarachnoid hemorrhage: a case-control study.
Greenberg JK, Guniganti R, Arias EJ, Desai K, Washington CW, Yan Y, Weng H, Xiong C, Fondahn E, Cross DT, Moran CJ, Rich KM, Chicoine MR, Dhar R, Dacey RG Jr, Derdeyn CP, Zipfel GJ.
Journal of Neurosurgery. 2016 Aug 5:1-8. [Epub ahead of print]

A Phase I proof-of-concept and safety trial of sildenafil to treat cerebral vasospasm following subarachnoid hemorrhage.
Washington CW, Derdeyn CP, Dhar R, Arias EJ, Chicoine MR, Cross DT, Dacey RG Jr, Han BH, Moran CJ, Rich KM, Vellimana AK, Zipfel GJ.
Journal of Neurosurgery. 2016 Feb;124(2):318-27. doi: 10.3171/2015.2.JNS142752.

Utility of Screening for Cerebral Vasospasm Using Digital Subtraction Angiography.
Arias EJ, Vajapey S, Reynolds MR, Chicoine MR, Rich KM, Dacey RG Jr, Dorward IG, Derdeyn CP, Moran CJ, Cross DT 3rd, Zipfel GJ, Dhar R.
Stroke. 2015 Nov;46(11):3137-41. doi: 10.1161/STROKEAHA.115.010081.

The unruptured intracranial aneurysm treatment score: a multidisciplinary consensus.
Etminan N, Brown RD Jr, Beseoglu K, Juvela S, Raymond J, Morita A, Torner JC, Derdeyn CP, Raabe A, Mocco J, Korja M, Abdulazim A, Amin-Hanjani S, Al-Shahi Salman R, Barrow DL, Bederson J, Bonafe A, Dumont AS, Fiorella DJ, Gruber A, Hankey GJ, Hasan DM, Hoh BL, Jabbour P, Kasuya H, Kelly ME, Kirkpatrick PJ, Knuckey N, Koivisto T, Krings T, Lawton MT, Marotta TR, Mayer SA, Mee E, Pereira VM, Molyneux A, Morgan MK, Mori K, Murayama Y, Nagahiro S, Nakayama N, Niemelä M, Ogilvy CS, Pierot L, Rabinstein AA, Roos YB, Rinne J, Rosenwasser RH, Ronkainen A, Schaller K, Seifert V, Solomon RA, Spears J, Steiger HJ, Vergouwen MD, Wanke I, Wermer MJ, Wong GK, Wong JH, Zipfel GJ, Connolly ES Jr, Steinmetz H, Lanzino G, Pasqualin A, Rüfenacht D, Vajkoczy P, McDougall C, Hänggi D, LeRoux P, Rinkel GJ, Macdonald RL.
Neurology. 2015 Sep 8;85(10):881-9. doi: 10.1212/WNL.0000000000001891.

Bicuspid aortic valves and thoracic aortic aneurysms in patients with intracranial aneurysms.
Goyal MS, Gottumukkala R, Bhalla S, Kates A, Zipfel GJ, Derdeyn CP.
Neurology. 2015 Jan 6;84(1):46-9. doi: 10.1212/WNL.0000000000001104.

Analysis of subarachnoid hemorrhage using the Nationwide Inpatient Sample: the NIS-SAH Severity Score and Outcome Measure.
Washington CW, Derdeyn CP, Dacey RG Jr, Dhar R, Zipfel GJ.
Journal of Neurosurgery. 2014 Aug;121(2):482-9. doi: 10.3171/2014.4.JNS131100.

Pattern not volume of bleeding predicts angiographic vasospasm in nonaneurysmal subarachnoid hemorrhage.
Raya A, Zipfel GJ, Diringer MN, Dacey RG Jr, Derdeyn CP, Rich KM, Chicoine MR, Dhar R.
Stroke. 2014 Jan;45(1):265-7. doi: 10.1161/STROKEAHA.113.002629.

Yield of catheter angiography after computed tomography negative, lumbar puncture positive subarachnoid hemorrhage [corrected].

Wallace AN, Dines JN, Zipfel GJ, Derdeyn CP.
Stroke. 2013 Jun;44(6):1729-31. doi: 10.1161/STROKEAHA.113.001234. Erratum in: Stroke. 2014 Jan;45(1):e10. 

Critical care management of patients following aneurysmal subarachnoid hemorrhage: recommendations from the Neurocritical Care Society’s Multidisciplinary Consensus Conference.
Diringer MN, Bleck TP, Claude Hemphill J 3rd, Menon D, Shutter L, Vespa P, Bruder N, Connolly ES Jr, Citerio G, Gress D, Hänggi D, Hoh BL, Lanzino G, Le Roux P, Rabinstein A, Schmutzhard E, Stocchetti N, Suarez JI, Treggiari M, Tseng MY, Vergouwen MD, Wolf S, Zipfel G; Neurocritical Care Society.
Neurocritical Care. 2011 Sep;15(2):211-40. doi: 10.1007/s12028-011-9605-9. Review.

Detection and monitoring of vasospasm and delayed cerebral ischemia: a review and assessment of the literature.
Washington CW, Zipfel GJ; Participants in the International Multi-disciplinary Consensus Conference on the Critical Care Management of Subarachnoid Hemorrhage..
Neurocritical Care. 2011 Sep;15(2):312-7. doi: 10.1007/s12028-011-9594-8. Review.

Neurofilament light chain levels in ventricular cerebrospinal fluid after acute aneurysmal subarachnoid haemorrhage.
Zanier ER, Refai D, Zipfel GJ, Zoerle T, Longhi L, Esparza TJ, Spinner ML, Bateman RJ, Brody DL, Stocchetti N.
Journal of Neurology, Neurosurgery, & Psychiatry. 2011 Feb;82(2):157-9. doi: 10.1136/jnnp.2009.177667.

Red blood cell transfusion increases cerebral oxygen delivery in anemic patients with subarachnoid hemorrhage.
Dhar R, Zazulia AR, Videen TO, Zipfel GJ, Derdeyn CP, Diringer MN.
Stroke. 2009 Sep;40(9):3039-44. doi: 10.1161/STROKEAHA.109.556159.

Vascular Malformations

Reynolds MR, Lanzino G, Zipfel GJ. Intracranial Dural Arteriovenous Fistulae – a Literature Review and Synthesis. 

Dural arteriovenous fistula-induced thalamic dementia: report of 4 cases.

Holekamp TF, Mollman ME, Murphy RK, Kolar GR, Kramer NM, Derdeyn CP, Moran CJ, Perrin RJ, Rich KM, Lanzino G, Zipfel GJ.
Journal of Neurosurgery. 2016 Jun;124(6):1752-65. doi: 10.3171/2015.5.JNS15473.

Borden-Shucart Type I dural arteriovenous fistulas: clinical course including risk of conversion to higher-grade fistulas.
Shah MN, Botros JA, Pilgram TK, Moran CJ, Cross DT 3rd, Chicoine MR, Rich KM, Dacey RG Jr, Derdeyn CP, Zipfel GJ.
Journal of Neurosurgery. 2012 Sep;117(3):539-45. doi: 10.3171/2012.5.JNS111257.

Cranial dural arteriovenous fistulae: asymptomatic cortical venous drainage portends less aggressive clinical course.
Strom RG, Botros JA, Refai D, Moran CJ, Cross DT 3rd, Chicoine MR, Grubb RL Jr, Rich KM, Dacey RG Jr, Derdeyn CP, Zipfel GJ.
Neurosurgery. 2009 Feb;64(2):241-7; discussion 247-8. doi: 10.1227/01.NEU.0000338066.30665.B2.

Ischemic Stroke

Effect of Hemodynamics on Stroke Risk in Symptomatic Atherosclerotic Vertebrobasilar Occlusive Disease.
Amin-Hanjani S, Pandey DK, Rose-Finnell L, Du X, Richardson D, Thulborn KR, Elkind MS, Zipfel GJ, Liebeskind DS, Silver FL, Kasner SE, Aletich VA, Caplan LR, Derdeyn CP, Gorelick PB, Charbel FT; Vertebrobasilar Flow Evaluation and Risk of Transient Ischemic Attack and Stroke Study Group..
JAMA Neurology. 2016 Feb;73(2):178-85. doi: 10.1001/jamaneurol.2015.3772.

Hemodynamic Features of Symptomatic Vertebrobasilar Disease.
Amin-Hanjani S, Du X, Rose-Finnell L, Pandey DK, Richardson D, Thulborn KR, Elkind MS, Zipfel GJ, Liebeskind DS, Silver FL, Kasner SE, Aletich VA, Caplan LR, Derdeyn CP, Gorelick PB, Charbel FT; VERiTAS Study Group.
Stroke. 2015 Jul;46(7):1850-6. doi: 10.1161/STROKEAHA.115.009215.

Palliative and end-of-life care in stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association.
Holloway RG, Arnold RM, Creutzfeldt CJ, Lewis EF, Lutz BJ, McCann RM, Rabinstein AA, Saposnik G, Sheth KN, Zahuranec DB, Zipfel GJ, Zorowitz RD; American Heart Association Stroke Council, Council on Cardiovascular and Stroke Nursing, and Council on Clinical Cardiology.
Stroke. 2014 Jun;45(6):1887-916. doi: 10.1161/STR.0000000000000015. Review.

Intravenous tissue-type plasminogen activator therapy is an independent risk factor for symptomatic intracerebral hemorrhage after carotid endarterectomy.
Vellimana AK, Yarbrough CK, Blackburn S, Strom RG, Pilgram TK, Lee JM, Grubb RL Jr, Rich KM, Chicoine MR, Dacey RG Jr, Derdeyn CP, Zipfel GJ.
Neurosurgery. 2014 Mar;74(3):254-61. doi: 10.1227/NEU.0000000000000261.

Symptomatic patients with intraluminal carotid artery thrombus: outcome with a strategy of initial anticoagulation.
Vellimana AK, Kadkhodayan Y, Rich KM, Cross DT 3rd, Moran CJ, Zazulia AR, Lee JM, Chicoine MR, Dacey RG Jr, Derdeyn CP, Zipfel GJ.
Journal of Neurosurgery. 2013 Jan;118(1):34-41. doi: 10.3171/2012.9.JNS12406.

See Dr Zipfel’s PubMed page.