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Alzheimer's Disease as a Neurovascular Inflammatory Disorder

Alzheimer's Disease as a Neurovascular Inflammatory Disorder

Tuesday, December 6, 2016

The New York Academy of Sciences

Growing evidence supports a role for neurovascular inflammation as a major factor in Alzheimer's Disease (AD) onset and progression. However, the scientific community has yet to label AD a vascular disease and questions remain about the viability of neurovascular inflammation as a potential therapeutic target. This symposium will evaluate clinical and preclinical data, and discuss critical barriers to understanding how to clinically test vascular-based hypotheses for the treatment of AD.

* Reception to follow.

Registration Pricing

Member (Student / Postdoc / Resident / Fellow)$25
Nonmember (Academia)$105
Nonmember (Corporate)$160
Nonmember (Non-profit)$105
Nonmember (Student / Postdoc / Resident / Fellow)$70

This event will also be broadcast as a webinar; registration is required.

Please note: Transmission of presentations via the webinar is subject to individual consent by the speakers. Therefore, we cannot guarantee that every speaker's presentation will be broadcast in full via the webinar. To access all speakers' presentations in full, we invite you to attend the live event in New York City where possible.

Webinar Pricing

Member (Student / Postdoc / Resident / Fellow)$15
Nonmember (Academia)$65
Nonmember (Corporate)$85
Nonmember (Non-profit)$65
Nonmember (Student / Postdoc / Resident / Fellow)$45


* Presentation times are subject to change.

Tuesday, December 6, 2016

8:00 AM

Registration and Continental Breakfast

8:15 AM

Navigating Successful Mentoring Relationships
Yaihara Fortis Santiago, PhD, The New York Academy of Sciences

9:00 AM

Welcome and Introductory Remarks
Sonya Dougal, PhD, The New York Academy of Sciences
Robert Nelson, PhD, MindImmune Therapeutics, Inc.

9:15 AM

Keynote Address:
The Gut–Brain Axis in Stroke and Dementia: Lessons from Animal Models
Costantino Iadecola, MD, Weill Cornell Medicine

10:00 AM

Cerebral Vascular Dysfunction in Aging and Alzheimer's Disease
Berislav Zlokovic, MD, PhD, Keck School of Medicine of USC

10:30 AM

Networking Coffee Break

11:00 AM

In Vivo Interrogation of Cerebral Microvascular Mural Cells in Health and Disease
Jaime Grutzendler, MD, Yale University

11:30 AM

The Brain Microvasculature: a Key Mediator of Neuroinflammation and Neuronal Injury in Alzheimer's Disease
Paula Grammas, PhD, University of Rhode Island

12:00 PM

Impairment of Glymphatic Function in the Aging Brain and Alzheimer's Disease
Jeffrey Iliff, PhD, Oregon Health & Science University

12:30 PM

The Interactive Effects of Peripheral Inflammation and APOE4 on AD Pathology in the Novel EFAD Mouse
Felecia M. Marottoli, University of Illinois at Chicago

* Presenter slides will not be included as part of the Webinar broadcast.

12:40 PM

In Vivo Imaging of Venous Side Microcirculation in Older Adults at 7T
C. Elizabeth Shaaban, MPH, University of Pittsburgh

12:50 PM

Networking Lunch and Poster Session
Poster Presenters will be present at their posters from 1:20 PM – 2:20 PM for Q&A

2:20 PM

Neurovascular Interactions: Mechanisms, Imaging, and Therapeutics
Katerina Akassoglou, PhD, University of California, San Francisco

2:50 PM

Anti-amyloid Immunotherapy: What Do the Blood Vessels Think?
Steven Greenberg, MD, PhD, Massachusetts General Hospital and Harvard Medical School

* Presenter slides will not be included as part of the Webinar broadcast.

3:20 PM

Networking Coffee Break

3:50 PM

Genetic and Biomechanical Evidence for Advanced Atherosclerosis Linking Vascular Cognitive Decline to Alzheimer's Disease
Robert Dempsey, MD, FACS, University of Wisconsin

4:20 PM

Panel Discussion:
Next Steps to New Research and Therapeutic Opportunities
Moderator: Heather Snyder, PhD, Alzheimer's Association
Panelists: Zorina Galis, PhD, National Institutes of Health / National Heart, Lung, and Blood Institute
Costantino Iadecola, MD, Weill Cornell Medicine
Steven Greenberg, Massachusetts General Hospital and Harvard Medical School

5:00 PM

F1000 Research Poster Prize Presentation

5:05 PM

Closing Remarks
Robert Martone, St. Jude Children's Research Hospital

5:10 PM

Networking Reception and Poster Viewing

6:10 PM

Symposium Adjourns


Robert Bell, PhD


Robert's lab within the Pfizer Neuroscience and Pain Research Unit has a strong focus in Neurovascular and Blood-Brain Barrier Biology. Following his undergraduate education at St. Bonaventure University and Oxford University, Robert worked at Socratech LLC, a small biotech company, with the primary focus of developing therapeutics for the treatment of neurodegenerative conditions. He then received a PhD in Pathology studying the role of cerebral vascular dysfunction in Alzheimer's disease under the supervision of Dr. Berislav Zlokovic at the University of Rochester. Before joining Pfizer in 2012, Robert completed an American Heart Association funded post-doctoral fellowship in cardiovascular biology in the Laboratory of Joseph Miano and also held a Research Assistant Professor position in the Department of Neurosurgery at the University of Rochester. Robert's research has elucidated several cellular and molecular mechanisms that regulate neurovascular functioning. Robert has authored over 30 scientific papers and was previously an associate editor for the Journal of Alzheimer's Disease. Robert's lab is working to identify and validate novel vascular-based targets for CNS disease and to enhance delivery of medicine across the blood-brain barrier.

Mercedes Beyna, MS


Mercedes Beyna, a researcher at Biogen, focuses on Drug Development mainly in the area of neurodegeneration. Captivated by neuroscience, she has worked in the field for over a decade, in both academic and industrial laboratory settings. Mercedes earned her undergraduate degree in Biology at Binghamton University and Master's Degree in Biology from New York University. As an active member of the Biochemical Pharmacology Discussion Group since 2010, she enjoys developing interesting and educational symposia.

Costantino Iadecola, MD

Weill Cornell Medicine

Dr. Iadecola is a clinician-scientist who works on the cellular and molecular mechanisms of neurovascular function, and on the overlap between stroke and dementia. Recent research efforts have focused on the role of adaptive and innate immunity in ischemic brain injury, and in the mechanism of the neurovascular dysfunction associated with vascular cognitive impairment and Alzheimer's dementia. Since 2012 he has been the Director of the Brain and Mind Research Institute, an academic unit with departmental privileges at Weill Cornell Medicine. He has published over 290 journal articles and plays a leadership role in national and international networks for stroke and dementia research. Dr. Iadecola is a recipient of two Javits Awards (2009 and 2015) from the National Institutes of Health, the Willis Award, the highest honor in stroke research bestowed by the American Heart Association (AHA), and of the Zenith Fellow Award from the Alzheimer's Association. In 2015 he received the Excellence Award for Hypertension Research (Novartis-AHA), in recognition of his seminal work on the impact of hypertension on the brain and Alzheimer's disease pathology. He is on several editorial boards, including the Annals of Neurology, Circulation Research, and the Journal of Cerebral Blood Flow and Metabolism, and has been active in various editorial capacities for Stroke, Hypertension, Circulation, the Proceedings of the National Academy of Sciences, and the Journal of Neuroscience. In 2015 he was elected to the Association of American Physicians. Dr. Iadecola is currently the Principal Investigator of several NIH grants and of grants from the Leon Levy Foundation and the Fondation Leducq.

Robert Martone

St. Jude Children's Research Hospital

Robert Martone conducts biomarker research and development with a focus on neuro-oncology in the Department of Pathology at St. Jude Children's Research Hospital. He was previously Neuroscience Therapeutic Area Lead for the Covance Biomarker Center of Excellence. He has extensive experience in the pharmaceutical industry leading neuroscience drug discovery and technology teams through all phases of discovery from target identification through clinical trials with expertise in both small molecule and protein therapeutics. He also has several years of academic research experience in molecular neurobiology, with a focus on the molecular genetics of familial neuropathies, and CNS tumor biomarker development.

Robert Nelson, PhD

MindImmune Therapeutics, Inc.

Dr. Robert Nelson has over 24 years of experience in pharmaceutical drug discovery and development, including work on both small molecule and biologic drug candidates. He is Vice President of Exploratory Biology and co-founder of MindImmune Therapeutics, Inc. based in the George and Anne Ryan Institute of Neuroscience at the University of Rhode Island. In conjunction with his responsibilities at MindImmune, Dr. Nelson is a Ryan Research Professor of Neuroscience at the University of Rhode Island. Prior to co-founding MindImmune, Dr. Nelson co-established and built one of the first Neuroinflammation units in the industry, which served as a primary focus of US research by Lundbeck. He was on the US research management team responsible for design and execution of drug discovery strategy (2010–2015). He created and headed a research division that identified peripheral immune mechanisms acting across the blood–brain barrier to propagate multiple neurological disorders, including Alzheimer's, Parkinson's, small vessel disease (SVD), and progressive MS. Dr. Nelson was project lead on several academic/industrial collaborations pursuing biologics-based therapeutic candidates for AD and progressive MS. Prior to joining Lundbeck, Dr. Nelson was an Associate Research Fellow in the CNS Discovery group at Pfizer, Inc. (1991–2009). While at Pfizer, Dr. Nelson was leader on a project that nominated for clinical development a prototype nNOS inhibitor CP-601,073 for stroke and stroke recovery. Dr. Nelson was also the biology lead on a joint collaboration with TransTech Pharmaceuticals that resulted in the nomination of a novel neuroinflammation-targeting compound currently in Phase III clinical trials for Alzheimer's disease. Dr. Nelson received his PhD from Northwestern University (Neuroscience program / Department of Psychology) in 1987, and was a Freudenberger Research Fellow in the laboratory of Dr. Huntington Potter at Harvard Medical School from 1989–1991, studying the role of CNS proteases in neurite outgrowth, astrocytic differentiation, and aberrant protein production/protein refolding.

Heather Snyder, PhD

Alzheimer's Association

Dr. Snyder is Senior Director of Medical and Scientific Operations at the Alzheimer's Association. She manages the Association's International Research Grant Program, through which the Association funds research around the world. Snyder oversees the Association's relationship with the leading disease journal in clinical neurology, Alzheimer's & Dementia: The Journal of the Alzheimer's Association, and its two companion open access journals. She is responsible for implementing the Alzheimer's Association Women's Alzheimer's Research Initiative and leads the Association's efforts to understand the role of vascular factors in Alzheimer's and dementia. Dr. Snyder received her PhD from Loyola University Chicago Stritch School of Medicine, her bachelor's degree in Biology and Religious Studies from The University of Virginia, and completed her postdoctoral fellowship at Children's Memorial Research Center, affiliated with Northwestern University, in Chicago. In addition, she serves on the board of directors for the Health Research Alliance and on the programmatic review committee US Army Medical Research and Materiel Command Peer Reviewed Alzheimer's Research Program.

Sonya Dougal, PhD

The New York Academy of Sciences

Caitlin McOmish, PhD

The New York Academy of Sciences


Katerina Akassoglou, PhD

University of California, San Francisco

Dr. Katerina Akassoglou is a Senior Investigator at the Gladstone Institute of Neurological Disease, and a Professor in the Department of Neurology at the University of California, San Francisco. Dr. Akassoglou has pioneered studies in the investigation of the role of the blood clotting factor fibrinogen in CNS autoimmunity, trauma, and neurodegeneration. Her aim is to understand the mechanisms that control the communication between the brain, immune and vascular systems with the goal to design novel therapies for neurologic diseases—and in particular, multiple sclerosis and neurodegenerative diseases. Her lab employs a multifaceted approach to her research, incorporating animal modeling, in vivo two-photon microscopy, drug discovery and pre-clinical translational research, and clinical biomarker studies. Dr. Akassoglou has published over 70 papers in peer-reviewed journals. Her laboratory had a long-standing funding from the NIH, the National Multiple Sclerosis Society, and the American Heart Association. Dr. Akassoglou was awarded by the White House the Presidential Early Career Award for Scientists and Engineers, the Abel Award from ASPET, the Dana Foundation Award in Brain and Immunoimaging, a EUREKA award from NINDS, The Marilyn Hilton Award for Innovation in Multiple Sclerosis Research by the Conrad N. Hilton Foundation, and the NINDS Research Program Award.

Robert Dempsey, MD

University of Wisconsin

Dr. Robert J. Dempsey, is the Manucher Javid Professor and Chairman of Neurological Surgery at the University of Wisconsin School of Medicine and Public Health. He specializes in cerebrovascular surgery of intracranial aneurysms, AVMs, carotid endarterectomy and brain tumors. With over 30 years of NIH funding, Dr. Dempsey has multiple research projects with a focus on cerebral ischemia, vascular cognitive decline, and repair of the injured brain. He has held grants from the NIH, VA, and the American Heart Association. In honor of his international mentoring of research scholars, the national resident research award in cerebrovascular surgery has been renamed the "Robert J Dempsey Cerebrovascular Resident Research Award". Dr. Dempsey is an award winning educator and mentor of medical students, residents and fellows worldwide. He is a 3-time winner of the UW Clinical Teaching Award as voted by the students. He Co-Directs the national course "Review in Neurobiology". He is a Past-President of the Society of Neurological Surgeons, the primary educational society in North America. He is presently the Chair of the Foundation for International Education in Neurological Surgery and has been awarded the Humanitarian Award for his international philanthropic work.

Zorina Galis, PhD

National Institutes of Health / National Heart, Lung, and Blood Institute

Zorina currently serves as the Chief of the NHLBI Vascular Biology and Hypertension Branch, overseeing a large extramural portfolio of investigator- and institute-initiated basic, translational, and clinical extramural research programs in basic vascular biology and the etiology, pathogenesis, prevention, diagnosis, and treatment of vascular diseases and hypertension. Previously she held tenured positions in academia in Cardiology, Biomedical Engineering, and Vascular Surgery, and in the pharmaceutical industry as the Chief Scientific Officer, Cardiovascular R&D at Eli Lilly and Co. Her independently funded research in the area of vascular biology and cardiovascular diseases, specifically pioneering new paradigms related to molecular mechanisms of vascular remodeling, acute cardiovascular events, and tissue engineering was the subject of numerous "most read" and "most cited" publications (Google Scholar profile, PubMed). Zorina has created and led numerous successful interdisciplinary teams and intra and inter-institutional alliances in academia, industry, and government, and is recognized as a scientific thought leader, a popular science educator and speaker. Zorina was trained in physics, biophysics, and cell biology (University of Bucharest, Romania), in pathology (McGill University School of Medicine, Montreal, Canada), and in vascular medicine (Harvard School of Medicine, Boston, USA).

Paula Grammas, PhD

University of Rhode Island

Paula Grammas, PhD, is the inaugural Executive Director of the George & Anne Ryan Institute for Neuroscience at the University of Rhode Island. Dr. Grammas is best known for her pioneering research into the role that blood vessels and inflammation play in the development of diseases, including Alzheimer's and other neurodegenerative diseases. A former professor of neurology and holder of the Mildred and Shirley Garrison Chair in Aging at the Texas Tech School of Medicine, she has received numerous awards for her research. Dr. Grammas has been the principal investigator or co-investigator on more than $24 million in research grants from the National Institutes of Health, the Alzheimer's Association, the American Foundation for AIDS Research, and other agencies and foundations. She has published more than 140 peer-reviewed research papers. She is the recipient of the Zenith Award from the Alzheimer's Association in recognition of her accomplishments as one of the nation's leading researchers on Alzheimer's disease.

Steven Greenberg, MD PhD

Massachusetts General Hospital and Harvard Medical School

Dr. Greenberg is Professor of Neurology at Harvard Medical School, Vice Chair of Neurology for Faculty Development and Promotions, and holds the John J Conway Endowed Chair in Neurology at Massachusetts General Hospital. He has served in many national and international leadership roles in the fields of stroke and neurology including principle investigator for the NINDS VCID biomarkers consortium coordinating center, president of the International CAA Association, chair of the NIH Acute Neurologic Injury and Epilepsy grant review committee, co-chair for the NINDS Alzheimer's Disease-Related Dementias Summit VCID subcommittee, and chair of the AHA International Stroke Conference. Dr. Greenberg has authored over 190 peer-reviewed research articles and over 70 chapters, reviews, and editorials in the areas of hemorrhagic stroke and small vessel brain disease, including authoritative review publications in Lancet Neurology on microbleeds (2009), microinfarcts (2012), and trial outcome markers (2014).

Jaime Grutzendler, MD

Yale University

Dr. Grutzendler obtained his MD at Universidad Javeriana in Bogota, Colombia where he was born and raised. He completed a medical internship in Internal Medicine and a residency in Neurology at Washington University/Barnes-Jewish Hospital in St. Louis. This was followed by a combined clinical and research fellowship in the Alzheimer Disease Research Center and the Department of Neurobiology at Washington University and further neurobiology research training at the Skirball Institute of New York University. Dr. Grutzendler's clinical interests focus on neurodegenerative disorders with special emphasis in dementias such as Alzheimer's disease. He also leads a research laboratory focused on understanding brain function and the cellular basis of neurological diseases. His lab uses advanced microscopy to visualize neurons, endothelium, astrocytes, pericytes, microglia and oligodendrocytes in living animals with the goal of exploring their dynamic behavior and learning how cell-cell interactions develop. He aims to understand how these interactions are disrupted in disease states such as in Alzheimer's disease, stroke and demyelination with the ultimate goal of designing new therapies for these conditions.

Costantino Iadecola, MD

Weill Cornell Medicine

Jeffrey Iliff, PhD

Oregon Health & Science University

Studying vascular physiology and the regulation of cerebral blood flow in his early career, Dr. Iliff completed his undergraduate degree at the University of Washington and his PhD in Physiology and Pharmacology at Oregon Health & Science University. Then, as a postdoc in the lab of Maiken Nedergaard at the University of Rochester Medical Center, Dr. Iliff helped to define the 'glymphatic' system, a brain-wide network of perivascular spaces that facilitates the clearance of wastes, including amyloid beta and tau, from the brain interstitium during sleep. More recently, Iliff's group has demonstrated that the glymphatic system fails in the aging brain and in the young brain after traumatic brain injury (TBI). These studies suggest that impairment of glymphatic function may be one factor that renders the aging brain vulnerable to protein aggregation and neurodegeneration and may link brain trauma early in life with the development of dementia in the decades that follow. Ongoing work in his lab seeks to define the molecular and cellular underpinnings of impaired glymphatic function in the aging and post-traumatic brain, and to use novel MRI-based imaging approaches to extend these findings into clinical Alzheimer's disease and post-traumatic populations.

Felecia M. Marottoli

University of Illinois at Chicago

Felecia Marottoli, BA, is a graduate student in the Tai laboratory at the University of Illinois at Chicago. Miss Marottoli's career goal is to identify novel mechanistic processes underlying Alzheimer's disease (AD) progression in order to develop therapeutic strategies. Her project focus is delineating the impact of three major AD risk factors on cerebrovascular dysfunction: APOE4, peripheral inflammation and Aβ. APOE4 is the greatest genetic risk factor for AD, peripheral inflammation is a cohesive link for known peripheral AD risk factors, and high Aβ levels are considered important for AD pathogenesis. Her novel data support that APOE4 and Aβ predispose the CV to damage in response to peripheral inflammation, leading to cognitive decline. These exciting data provide a novel mechanism underling AD progression, and support the development of therapeutic strategies targeting the CV for these high risk AD groups.

C. Elizabeth Shaaban, MPH

University of Pittsburgh

Beth Shaaban is a PhD student in the Department of Epidemiology at the University of Pittsburgh Graduate School of Public Health. She is specializing in Neuroepidemiology and concurrently obtaining a graduate certificate in neuroscience from the Center for the Neural Basis of Cognition, a combined program of the University of Pittsburgh and Carnegie Mellon University. She is the PI of her NIA funded F31/NRSA individual training grant entitled "Pathways of beneficial effects of a physical activity intervention on hippocampal atrophy among older adults." Her research focuses on the promotion of neurovascular integrity for the prevention of cognitive disorders in aging. Beth previously worked at the University of Pittsburgh NIA funded Alzheimer Disease Research Center as the Neuropsychology Program Coordinator. She served for two years as the President of the Doctoral Student Organization at the Graduate School of Public Health and currently serves as the chair of the Mentors, Advisors, Peers Committee of the Pittsburgh chapter of Women in Bio.

Heather Snyder, PhD

Alzheimer's Association

Berislav Zlokovic, MD PhD

Keck School of Medicine of USC

Berislav V. Zlokovic is director of the Zilkha Neurogenetic Institute, professor and chair of the Department of Physiology & Biophysics at the Keck School of Medicine of USC, and professor of biological sciences at the Dornsife College of Letters, Arts and Sciences. Zlokovic has a life-long career in studying the role of cerebral blood vessels in Alzheimer’s disease and stroke. Discoveries of his research team have contributed to clinical trials for Alzheimer’s disease based on cerebrovascular protection and clearance of amyloid-beta from the brain and/or blockade of its vascular transport into the brain, and phase 2 studies in stroke patients based on activated protein C brain protection. He received MetLife Award, Potamkin Prize, and MERIT (NIA) and Javits (NINDS) awards. He is fellow of the AAAS, the Danna Alliance for Brain Initiative, the Serbian Academy of Sciences and Arts, and the European Academy of Sciences. He made Thomson Reuters list of "The World's Most Influential Scientific Minds" in 2014 for ranking in one percent of the most-cited authors in neurosciences from 2002 to 2012. In 2016, Zlokovic made again the Thomson Reuters list of top highly cited researchers in neurosciences and behavioral sciences.


Grant Support

Funding for this conference was made possible, in part, by R13NS098718 from the National Institute of Neurological Disorders and Stroke. Co-funding has been provided by the National Heart, Lung, and Blood Institute. The views expressed in written conference materials or publications and by speakers and moderators do not necessarily reflect the official views of the National Institutes of Health; nor does mention by trade names, commercial practices, or organizations imply endorsement by the U.S. Government.

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Alzheimer's Association

H. Lundbeck A/S

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Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring

Alzheimer's & Dementia: Translational Research & Clinical Interventions

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American Federation for Aging Research



Dana Foundation

The Gerontological Society of America

Journal of Neuroimmunology

LEAD Coalition

Lewy Body Dementia Association (LBDA)


Neurobiology of Aging


The Biochemical Pharmacology Discussion Group is proudly supported by:

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Premiere Supporter

  • Pfizer


The Gut–Brain Axis in Stroke and Dementia: Lessons from Animal Models
Costantino Iadecola, MD, Weill Cornell Medicine

Owing to the blood–brain barrier, the brain has traditionally been considered an "immune privileged" organ, nearly impenetrable to immune cells. However, a growing body of evidence indicates that cells of the immune system traffic in and out of the brain and can have either beneficial or detrimental effects on the brain tissue. The gut is a major reservoir of immune cells, and is emerging as a key player in acute and chronic brain pathologies. Whereas innate immunity contributes to the acute phase of the tissue damage associated with experimental cerebral ischemia, immune cells originating from the gut protect the brain from impending damage in models of intestinal dysbiosis. In addition, intestinal immune cells play a critical role in the vascular dysregulation associated with cognitive impairment, a model of vascular dementia. The realization that the gut immune system is critically involved in the pathobiology of major brain diseases provides the opportunity to modulate immune function with the goal to reset the balance between its protective and destructive effects, and to develop new approaches for the prevention or treatment of stroke and dementia.

Cerebral Vascular Dysfunction In Aging and Alzheimer's Disease
Berislav V. Zlokovic, Keck School of Medicine, University of Southern California

Blood vessels in the brain are organized with surprising precision, patterned in parallel with the major brain circuits tasked with sensation, memory and motion. This tight interrelationship may reflect key functional roles in neuronal normal function, brain aging and brain diseases such as Alzheimer's disease (AD). I will examine the cellular and molecular composition of the blood–brain barrier (BBB) and the role of different cell types (e.g., endothelial cells, pericytes, astrocytes) and molecular pathways within the neurovascular unit in cerebral vascular dysfunction and neurodegeneration in rare human monogenic disorders, and complex neurological diseases such as AD. Will make comparison with findings in animal transgenic models. Next, will discuss multiparametric magnetic resonance imaging findings in the living human brain and animal model systems, and molecular biomarkers of BBB integrity in relation to changes in brain connectivity, cognition and behavioral deficits. Finally, I will briefly review the effects of AD risk genes (e.g., APOE4, PICALM, CLU) on cerebral vascular and BBB dysfunction, and targets and treatments directed at cerebral blood vessels that have advanced to Phase 3 and Phase 2 clinical studies in AD and stroke patients, respectively, based on our preclinical findings.

In Vivo Interrogation of Cerebral Microvascular Mural Cells in Health and Disease
Jaime Grutzendler, MD, Yale University

Microvascular mural cells (smooth muscle and pericytes) play critical roles in neuropathology and neurovascular physiology. However, the lack of precise markers to distinguish them from each other has limited our understanding of their precise functions. In this talk, I will present recent methodologies that we have developed and implemented to image and manipulate mural cells in their intact in vivo microenvironment. Insights gained with these strategies have potentially important implications for understanding mechanisms of neurovascular coupling and blood flow regulation as well as the pathophysiology of cerebrovascular and neurodegenerative disorders.

The Brain Microvasculature: A Key Mediator of Neuroinflammation and Neuronal Injury in Alzheimer's Disease
Paula Grammas, PhD, University of Rhode Island

The Alzheimer's disease (AD) epidemic proceeds unabated. Estimates suggest 5.4 million Americans and 36 million people world-wide have AD. Although the idea that vascular defects are important in disease pathogenesis was suggested over 30 years ago, an active role for the cerebrovasculature in the pathogenesis of AD has not been well explored. A dysfunctional vasculature could drive pathogenic events leading to neuronal injury and death in a number of ways. Brain vascular endothelial cells regulate the neuronal milieu both by their blood-brain barrier function as well as by their synthetic capabilities. Because disturbance in cerebrovascular metabolic function, and resulting altered synthesis of bioactive species, can affect neuronal viability it has been our working hypothesis that a dysfunctional vasculature contributes to neuronal cell death in AD by producing neurotoxic factors. By examining isolated brain microvessels in AD we have documented that the cerebral microcirculation is indeed a rich source of neurotoxins (thrombin, nitric oxide), inflammatory cytokines, and proteases. Expression of these diverse mediators is consistent with the process of vascular activation, reflecting the transition of endothelial cells from a quiescent to highly synthetic phenotype. The relevance of this pathologic activation and transition is supported by our experiments in AD animal models demonstrating that inhibiting vascular activation reduces expression of neurotoxic factors and improves cognition. New thinking about AD pathogenesis and novel, effective treatments are urgently needed. Taken together, our work suggests that vascular activation is an unrecognized and heretofore unexplored target for the development of AD therapeutics.

Impairment of Glymphatic Function in the Aging Brain and Alzheimer's Disease
Jeffrey Iliff, PhD, Oregon Health & Science University

While aging is the strongest risk factor for the development of Alzheimer's disease, disruption of normal sleep patterns has long been associated with aging and more recently has been associated with the development of Alzheimer's pathology. Recently, a brain-wide perivascular network termed the 'glymphatic' system, has been characterized that facilitates the clearance of interstitial solutes including amyloid beta and tau from the brain. Interestingly, this function was active primarily in the sleeping brain, and is impaired in both the aging and the post-traumatic brain, suggesting one possible basis for the link between aging, sleep disruption and neurodegenerative processes. New data from human clinical subjects suggests that changes in the in elements of the glymphatic system, including the astroglial water channel aquaporin-4 (AQP4) are associated with Alzheimer's status and pathology, and neurocognitive decline. These findings suggest that glymphatic insufficiency may be one feature of the aging brain that renders it vulnerable to protein mis-aggregation in neurodegenerative conditions such as Alzheimer's.

The Interactive Effects of Peripheral Inflammation and APOE4 on AD Pathology in the Novel EFAD Mouse
Felecia M. Marottoli, University of Illinois at Chicago

The scarcity of effective therapeutic approaches for Alzheimer's disease (AD) underscores the vital importance of identifying novel pathways of AD progression. The re-emergence of cerebrovascular (CV) dysfunction as a major contributing factor in cognitive decline has become an attractive focal point. The CV serves as a regulatory physical and metabolic interface between the CNS and periphery, making it prudent to determine how it is affected by AD risk factors, specifically APOE genotype and peripheral inflammation. APOE4 is the strongest genetic risk factor of AD, conferring up to a 12-fold increase in risk compared to APOE3. Peripheral inflammation is a primary underlying commonality among known non-genetic, AD risk factors including diabetes, hypertension, hypercholesterolemia, and atherosclerosis. Furthermore, not only is peripheral risk factor-induced cognitive decline greater in human APOE4 carriers, but both APOE4 and peripheral inflammation are able to independently induce CV dysfunction. Therefore, we hypothesize that peripheral inflammation causes CV dysfunction and cognitive deficits in APOE4 carriers. In this study, chronic, low-level inflammation was induced in EFAD mice. EFAD mice are a novel, AD-relevant model of APOE-modulated Aβ pathology that express human APOE3 or APOE4 and overproduce human Aβ via the expression of 5 Familial Alzheimer's disease mutations (5×FAD). EFAD carriers [5×FAD+/−/APOE+/+ (EFAD+)] and non-carrier, littermate controls [5×FAD−/−/APOE+/+ (EFAD−)] enable the comparison of the effects of inflammation with or without high levels of Aβ present. Peripheral inflammation-induced cognitive decline and CV dysfunction was observed only in E4FAD+ mice. Biochemical assessment demonstrated increased soluble and insoluble (formic acid-extracted) Aβ42 levels, as well as soluble apoE levels in the hippocampus of E4FAD+ mice exposed to peripheral immune challenge. These data imply that APOE4 genotype and Aβ prime the CV to damage by peripheral inflammation, leading to increased Aβ levels and cognitive dysfunction. Therefore, prevention of peripheral inflammation and improvement of vascular health are attractive and viable treatments for AD.
Coauthors: Kevin P. Koster, Riya Thomas, and Leon M. Tai, Department of Anatomy and Cell Biology, University of Illinois at Chicago.

In Vivo Imaging of Venous Side Microcirculation in Older Adults at 7T
C. Elizabeth Shaaban, MPH, University of Pittsburgh

Cerebral small vessel disease (SVD) increases vulnerability to Alzheimer's disease (AD) neuropathology. Traditional neuroimaging markers of SVD focus on late-stage changes and typically ignore venous side circulation. However, venules are the site of initial neuroinflammatory response and may be implicated in β amyloid deposition and clearance. Therefore, we aimed to adapt a method to characterize venules in older adults and assess relationships with variables of relevance to SVD and AD. Lengths of tortuous and straight venules were determined in periventricular regions of interest on susceptibility-weighted imaging (SWI). Tortuosity ratio was defined as total tortuous venular length over total straight venular length. WMH burden (visually rated from 0 to 3) and number of microbleeds (0, 1, >1) were also determined. Differences in tortuous and straight venular lengths were evaluated. Using Spearman correlations, we assessed relationships of tortuosity ratio with other neuroimaging markers of SVD (WMH and microbleeds), demographic variables, APOE4, molecular markers, pulse pressure, physical activity, and Modified Mini-Mental State examination. Participants had 42% more tortuous venular tissue than straight (median [95% CI]: 1.42 [1.13, 1.62]). APOE4 allele was associated with greater tortuous venular length (rho=0.454, p=0.001), and these results were robust to adjustment for confounders and multiple comparisons. Associations with sex and vascular endothelial growth factor did not survive adjustment. Other associations were not significant. SWI imaging of venules at 7T provides a method of evaluating vascular characteristics of potential relevance to both SVD and AD. Longitudinal studies examining impact of APOE4 and temporal sequence of damage are warranted.
Coauthors: Howard Jay Aizenstein1, Dana R. Jorgensen1, Rebecca L. MacCloud1, Nicole A. Meckes1, Kirk I. Erickson1, Nancy W. Glynn1, Joseph Mettenburg1, Ronald Cohen2, Jack Guralnik3, Anne B. Newman1, Tamer S. Ibrahim1, Paul J. Laurienti4, Abbe N. Vallejo1,5, and Caterina Rosano1.
1. University of Pittsburgh
2. University of Florida, Gainesville
3. University of Maryland School of Medicine, Baltimore
4. Wake Forest University School of Medicine, Winston-Salem
5. Children's Hospital of Pittsburgh

Neurovascular Interactions: Mechanisms, Imaging, and Therapeutics
Katerina Akassoglou, PhD, Gladstone Institutes of Neurological Disease, San Francisco and University of California, San Francisco

The neurovascular interface fundamentally changes during CNS diseases due to increased blood–brain barrier permeability and influx of plasma proteins in the CNS parenchyma. Studying neurologic diseases through the multidisciplinary prism of vascular biology, immunology, and neuroscience could be critical for the identification of novel mechanisms of disease, discovery of imaging tools and therapeutic treatments for a wide range of neurologic diseases characterized by BBB disruption. We made unanticipated discoveries on the functional role of BBB disruption in CNS autoimmunity, glial cell activation, and neurodegeneration. We identified leakage of blood proteins in the brain and neurotrophin receptor signaling as novel molecular mediators at the neurovascular interface that regulate glial–neuron cross-talk and the communication between the brain and the immune system. Furthermore, we developed novel methods for high-resolution two-photon microscopy of the neurovascular interface in vivo. Our aim is to understand the mechanisms that control the communication between the brain, immune and vascular systems with the ultimate goal to design novel therapies for neurologic diseases. Molecular mediators at the neurovascular interface that contribute to neurodegeneration will be discussed.

Anti-amyloid Immunotherapy: What Do the Blood Vessels Think?
Steven Greenberg, MD PhD, Massachusetts General Hospital and Harvard Medical School

Despite mixed results to date, anti-amyloid immunotherapy remains the most advanced and promising disease-modifying approach for Alzheimer's disease. The major adverse effects associated with anti-amyloid immunotherapy—vasogenic edema and microbleeding, collectively known as the amyloid-related imaging abnormalities (ARIA)—appear to arise from the cerebrovasculature. This presentation will address the vascular response to anti-amyloid immunotherapy, in particular the role of cerebrovascular amyloid deposition (cerebral amyloid angiopathy, CAA) in the pathogenesis of ARIA. Strong connections between CAA and ARIA are suggested by the CAA-related inflammation syndrome, in which an ARIA-like picture is triggered by spontaneously generated anti-amyloid autoantibodies. A recently completed pilot trial of anti-amyloid immunotherapy as a candidate treatment for CAA adds further intriguing information on the range of possible vascular responses to this treatment approach.

Genetic and Biomechanical Evidence for Advanced Atherosclerosis Linking Vascular Cognitive Decline to Alzheimer's Disease
Robert Dempsey, MD, FACS, University of Wisconsin School of Medicine and Public Health

Introduction: Microvascular changes in stroke carry tremendous pathology. Imaging suggests as many as 11 million "silent strokes" per year. We present a study of patients with advanced atherosclerotic disease to determine the relationship of genetic upregulations, atherosclerotic instability, microvascular changes, and vascular cognitive decline.
Methods: Atherosclerotic plaques from symptomatic and asymptomatic patients are studied for gene upregulation. We have developed a noninvasive ultrasound measure for carotid plaque instability quantifying stability during arterial pulsation. Measures include carotid plaque instability, presence of brain microemboli, presence of remote stroke or TIA, brain white matter changes, microvascular changes in plaques, and vascular cognitive decline.
Results: We show upregulation of 27 gene transcripts related to small vessel angiogenesis confirmed by real time PCR. We show that symptomatic plaques show 2–3 fold fissuring by microvascular pathology. A direct relationship is seen between the degree of plaque instability and vascular cognitive decline regardless of degree of stenosis or preoperative overt stroke. Abnormal strain and presence of microemboli directly correlates to cognitive decline and white matter burden on MRI. Preliminary evidence suggests that combined medical and surgical interventions may stabilize cognition.
Conclusion: Vascular cognitive decline is a major symptom of cerebrovascular disease that is related to advanced atherosclerotic disease and advanced by physical instability of these plaques, new microvessel formation and related white matter changes in the brain. Cognitive changes can be measured objectively and identified prior to the presence of overt stroke suggesting a progression of vascular cognitive decline to later dementia such as Alzheimer's.
Coauthors: T. Varghese, B. Herman, D. Jackson, S. Herman, S. Johnson, C. Mitchell, S. Wilbrand, R. Vemuganti, University of Wisconsin School of Medicine and Public Health; and B. Rock, University of Alabama.

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