Targeting the Vasculature in Alzheimer's Disease and Vascular Cognitive Impairment

Targeting the Vasculature in Alzheimer's Disease and Vascular Cognitive Impairment

Friday, May 4, 2012

The New York Academy of Sciences

Vascular pathology has been long established, but is under-appreciated, as a contributing factor in Alzheimer's disease (AD). It is likely that vascular alterations are both a cause and a consequence of neuronal loss. This conference will present the current clinical knowledge of the vascular connection to AD pathogenesis and will highlight novel vascular approaches to intervention that can be applied to Alzheimer's disease therapeutic development.

Networking reception to follow.

Registration Pricing

Member$25
Student / Postdoc / Fellow Member$10
Student / Postdoc / Fellow Nonmember$40
Nonmember Academic$60
Nonmember Not for Profit$60
Nonmember Corporate$80

 

Presented by

  • Alzheimer's Drug Discovery Foundation
  • The New York Academy of Sciences

Agenda

* Presentation times are subject to change.


Friday, May 4, 2012

8:30 AM

Registration and Continental Breakfast

8:55 AM

Welcome
Jennifer Henry, PhD, The New York Academy of Sciences

9:00 AM

Opening Remarks
Howard Fillit, MD, The Alzheimer’s Drug Discovery Foundation

Session I. Overview and Pathogenic Mechanisms

9:15 AM

Vascular Contributions to Cognitive Impairment and Dementia
Philip Gorelick, MD, Hauenstein Neuroscience Institute

9:35 AM

Q&A session

9:45 AM

The Overlap between Neurodegenerative and Vascular Factors in Dementia
Costantino Iadecola, PhD, Weill Cornell Medical College

10:05 AM

Q&A session

10:15 AM

Gain-of-Function Somatic Mutations Initiate the Vascular Damage that Leads to Alzheimer's Dementia: A Hypothesis
Vincent Marchesi, MD, PhD, Yale University

10:35 AM

Q&A session

10:45 AM

Understanding Cerebral Amyloid Angiopathy
Steven Greenberg, MD, PhD, Harvard Medical School

11:05 AM

Q&A session

11:15 AM

Coffee Break

Session II. Vascular Outcomes in Clinical Trials

11:45 AM

MRI Markers of Vascular Cognitive Impairment
Bruce R. Reed, PhD, UC Davis Alzheimer's Disease Research Center

12:05 PM

Q&A session

12:15 PM

The effects of Abeta Immunotherapy on the Vasculature
Kejal Kantarci, MD, Mayo Clinic

12:35 PM

Q&A session

12:45 PM

Hypertension, Cognitive Decline and Dementia: The Hidden Role of Obstructive Sleep Apnea
Gustavo C. Román, MD, Methodist Neurological Institute

1:15 PM

Lunch Break

Session III. Vascular Targets for Alzheimer’s Disease Drug Discovery

2:15 PM

TBI and AD: Vascular Coag-Inflammatory Pathways and Therapeutic Targets
Barry W. Festoff, MD, University of Kansas Medical Center and pHLOGISTIX LLC

2:35 PM

Q&A session

2:45 PM

Leukocyte Plugging of Capillaries Reduces Brain Blood Flow in Mouse Models of Alzheimer's Disease
Chris Schaffer, PhD, Cornell University

3:05 PM

Q&A session

3:15 PM

Fibrinogen and β-amyloid Association Alters Thrombosis and Fibrinolysis: A Possible Contributing Factor to Alzheimer's Disease
Sidney Strickland, PhD, Rockefeller University

3:45 PM

Coffee Break

4:15 PM

Guarding Vascular Health with High Density Lipoproteins
Cheryl Wellington, PhD, University of British Columbia

4:35 PM

Q&A session

4:45 PM

Closing Remarks
Howard Fillit, MD, ADDF

5:00 PM

Networking Reception

6:00 PM

Close

Speakers

Organizers

Howard Fillit, MD

Alzheimer's Drug Discovery Foundation

Howard Fillit, MD, a geriatrician, neuroscientist and a leading expert in Alzheimer's disease, is the founding Executive Director of the Alzheimer's Drug Discovery Foundation (ADDF). The ADDF's mission is to accelerate the discovery and development of drugs to prevent, treat and cure Alzheimer's disease, related dementias and cognitive aging.

Dr. Fillit has had a distinguished academic medicine career at The Rockefeller University and The Mount Sinai School of Medicine where he is a clinical professor of geriatrics and medicine and professor of neurobiology. He is a Co-author of more than 250 scientific and clinical publications, and is the senior editor of the leading international Textbook of Geriatric Medicine and Gerontology. Previously, Dr. Fillit was the Corporate Medical Director for Medicare at New York Life, responsible for over 125,000 Medicare managed care members in five regional markets. Dr. Fillit has received several awards and honors including the Rita Hayworth Award for Lifetime Achievement. He also serves as a consultant to pharmaceutical and biotechnology companies, health care organizations and philanthropies.

Jennifer Henry, PhD

The New York Academy of Sciences

Speakers

Barry W. Festoff, MD

University of Kansas Medical Center and pHLOGISTIX LLC

Barry W. Festoff, MD, is Professor of Neurology, Integrative Physiology and Pharmacology at the University of Kansas Medical Center (KUMC), where he has been since 1976, when he joined KUMC and the VA Medical Center in Kansas City (KCVAMC). He founded the Neurology Service at the VAMC, was its first Chief and Director of the Neurobiology Research Laboratory. His research has focused on connections between CNS trauma and neurodegeneration with an emphasis on coagulation proteases, principally thrombin, its regulation and its expression in the CNS. Thrombin inhibitors and regulators, such as protease nexin I (PN-I) and thrombomodulin (TM,) have featured in his group's studies emphasizing neuroinflammation. He retired from the VA in October 2010 and founded pHLOGISTIX LLC, a Delaware company with strategies to harness neuroinflammation in CNS injury and other conditions.

Philip B. Gorelick, MD, MPH

Hauenstein Neuroscience Institute

Dr. Philip B. Gorelick is the Medical Director of the Hauenstein Neuroscience Center, Saint Mary's Health Care, Grand Rapids, MI (February 6, 2012–present) and previously was the John S. Garvin Professor and Head, Department of Neurology and Rehabilitation, University of Illinois College of Medicine at Chicago (2003–Jan. 2012). Dr. Gorelick attended the Cardinal Stritch School of Medicine at Loyola and graduated in 1977. He completed Neurology Residency at Loyola and Hines VAH (1978–1981). After residency, he served as a Stroke Fellow under Louis R. Caplan, M.D., at Michael Reese Hospital as part of the University of Chicago Neurology Program (1981–1982). Dr. Gorelick then served as the Director of the University of Illinois Stroke Service in the Department of Neurology (1982–1985). He was later the Director of the Stroke Service at Michael Reese Hospital (1985–1991) and during this time received a MPH in epidemiology and biostatistics at University of Illinois School of Public Health. He was the Director of the Stroke and Neurological Critical Care Service at Rush Medical Center (1991–2003) where he was awarded an endowed chair in Neurology—the Jannotta Presidential Chair. Dr. Gorelick is board-certified in Neurology and Vascular Neurology.Dr. Gorelick is well known in national and international circles as a world leader in stroke prevention. He has developed innovative studies for identification of risk factors for stroke, prevention of first and recurrent stroke, and the elucidation of risk factors and mechanisms for vascular forms of cognitive impairment (VCI). His important work has been recognized by major stroke organizations worldwide as he has received the Feinberg Award for Excellence in Clinical Stroke 2004 from the American Heart Association and the National Stroke Association (NSA) Visionary in Stroke Award. He has also held the Daniel Gainey Professorship 2005 at Mayo Clinic, the Henry Barnett 2005 Lectureship from the Canadian Stroke Network, and the Stooplemoor Visiting Lectureship in Neurology (2009) at University of Iowa. Dr. Gorelick was awarded a grant from the World Federation of Neurology in 2011 to develop a prototype registry of provision of neurological services worldwide and to develop interventions to improve neurological services and treatment in developing countries. He currently directs the Clinical Coordinating Center for the US DIAS Trial and recently 1st-authored a AHA/ASA guidance statement on the vascular burden of cognitive impairment (Gorelick PB et al. Stroke 2011; 42: 2672–2713). He also holds the distinction of continuous funding from the NIH for his research work over an 18-year period. Dr. Gorelick has published over 250 peer-reviewed articles and has edited 6 books in his field with 2 more in development.

Steven M. Greenberg, MD, PhD

Harvard Medical School

Dr. Greenberg is Director of the Hemorrhagic Stroke Research Program at Massachusetts General Hospital and Professor of Neurology at Harvard Medical School. Initiated in 1994, the Hemorrhagic Stroke Research Program has become internationally recognized as a leading authority on the causes, diagnosis, and treatment of cerebral amyloid angiopathy. Dr. Greenberg has authored over 100 research articles and 50 chapters, reviews, and editorials in the areas of hemorrhagic stroke and small vessel brain disease, served as principal investigator on multiple national research grants, and in leadership positions at national and international conferences on hemorrhagic stroke and vascular cognitive impairment. He currently serves as Chair of the International Stroke Conference, Chair of the NINDS Stroke Progress Review Group's Vascular Cognitive Impairment subsection, and Director of Faculty Development for the Massachusetts General Hospital Department of Neurology.

Costantino Iadecola, MD

Weill Cornell Medical College

Costantino Iadecola, M.D., the G. C. Cotzias Distinguished Professor of Neurology and Neuroscience and Chief of the Division of Neurobiology at Weill Cornell Medical College, is a clinician-scientist who works on the cellular and molecular mechanisms of cerebral ischemia, and on the interface between stroke and dementia. Dr. Iadecola has published over 220 peer-reviewed papers and plays a leadership role in several research organizations and funding agencies. He chairs the scientific board of the Fondation Leducq and is an advisor to the European Stroke Network and to the Institute of Stroke and Dementia Research (Munich, Germany). He is a recipient of the Willis Award, the highest honor in stroke research bestowed by the AHA, and of the Zenith Fellow Award from the Alzheimer's Association.

Kejal Kantarci, MD

Mayo Clinic

Kejal Kantarci is Associate Professor of Radiology at the division of Neuroradiology Mayo Clinic. Dr. Kantarci’s research focuses on identifying imaging markers for early diagnosis and differential diagnosis of dementia. She has authored 50 peer-reviewed publications, 8 book chapters and given invited lectures in 22 national and international courses and symposia. She is a charter member of the NIH /CSR Biomedical Imaging and Technology Study Section. She received the New Investigator Award from the Alzheimer's Association in 2003 and Paul Beeson Award in Aging from the National Institutes of Aging, American Federation of Aging Research, John Hardford Foundation, Atlantic Philantropies, and Starr Foundation in 2007. Her research program has been funded continuously by the Alzheimer’s Association and the National Institutes of Health since 2003.

Vincent Marchesi, MD, PhD

Yale School of Medicine

Vincent Marchesi is a Professor of Pathology and Director of the Boyer Center for Molecular Medicine at Yale University. He received a BA and MD from Yale and a D. Phil from Oxford University and is a member of the National Academy of Sciences and the Institute of Medicine.

Bruce R. Reed, PhD

UC Davis Alzheimer's Disease Research Center

Dr. Reed is Professor of Neurology at the University of California, Davis and serves as Associate Director of the UC Davis Alzheimer's Disease Center. Dr. Reed received his B.A. Carleton College and his Ph.D. in Clinical Psychology from SUNY Stony Brook. He has published over 100 peer-reviewed publications on the neuropsychology of cognitive aging and dementia. His work on the contributions of vascular factors to cognitive impairment in aging has been funded by NIA since 1993. He recently served as Chair of the NIH Clinical Neuroscience Neurodegeneration study section and as panel member for the NINDS Stroke Progress Review Group's Vascular Cognitive Impairment subsection.

Gustavo C. Román, MD

Methodist Neurological Institute

Prior to joining the Methodist Hospital, Dr. Román was Professor of Neurology, University of Texas Health Science Center at San Antonio (UTHSCSA), and Neurologist at the Veterans Administration Audie L. Murphy Hospital in San Antonio, Texas, USA. Dr. Román is a medical graduate from the National University of Colombia with training in Neurology at the Salpêtrière Hospital, University of Paris, France, and at the University of Vermont, Burlington, VT. Dr. Román was Interim Chairman of Neurology and Neurosurgery at Texas Tech University in Lubbock, Texas. He served as Chief of the Neuroepidemiology Branch at the prestigious US National Institutes of Health. At the NIH, he organized the international workshop that defined the criteria for Vascular Dementia for research studies (NINDS-AIREN Criteria). He created an international research network in neuroepidemiology, with participants from Latin America, Europe, India and China that to this day continues to yield data. Dr. Román received the Commendation Medal of the US Department of Health and Human Services and the Distinguished Alumnus Medal of his Alma Mater. He is Honorary Member of the neurological societies of France, Spain, Panama, Dominican Republic, Cuba, Venezuela, and Austrian Society of Tropical Medicine. Dr. Román was elected Fellow of the American Neurological Association, American Academy of Neurology, American College of Physicians, Royal Society of Medicine (London), Royal Society of Tropical Medicine (London) and the Colombian Academy of Medicine. He is Honorary President of the Pan American Society of Neuroepidemiology, and Honorary Professor, Universita degli Studi di Ferrara (Italy). He has participated in the International Affairs committee of the American Academy of Neurology and is Chair Elect of the Neuroepidemiology Section. In 2008, Dr Román was elected Trustee to the Board of Directors of the World Federation of Neurology. He has served as Associate Editor of The Journal of the Neurological Sciences, official journal of the WFN, Ad Hoc Member of the Continuing Education Committee, Chair of the Research Group (RG) on Neuroepidemiology, Secretary for the Americas of the RG on Tropical Neurology, member of the RG on Dementia, and Secretary of the Environmental Neurology RG. Dr Román is fluent in Spanish, English and French, and has published 16 books, 35 chapters in books and more than 300 journal articles. He organized the International Congress on Vascular Dementia (Geneva, 1999, Salzburg 2002) and Vas-Cog 2007 (San Antonio, Texas, USA). He is past Editor-in-Chief of Neuroepidemiology (2000-2007) and editorial board member of Dementia and Geriatric Cognitive Disorders, Clinical Neurology and Neurosurgery, Revista de Neurología, Neurología, Gaceta Médica de México, and ad-hoc reviewer for numerous journals. Dr. Román is an internationally recognized expert in vascular dementia, cognitive neurology, neuroepidemiology and tropical neurology. He served as advisor to the FDA and is a current reviewer for the Aging Systems and Geriatrics Study Section of the NIH.

Chris B. Schaffer, PhD

Cornell University

Chris Schaffer received his undergraduate degree from the University of Florida in 1995 and his PhD from Harvard University, working with Eric Mazur, in 2001. Both of his degrees are in Physics. As a post-doc at UCSD, Chris worked with David Kleinfeld in the Physics and Neuroscience departments. He is currently an Associate Professor at Cornell University in the Department of Biomedical Engineering. His research has centered on the development of optical tools for in vivo manipulation of biological structures and the use of these tools to study the role of cortical microvascular lesions in neurological disease, with a current focus on the role of microvascular disruptions in Alzheimer’s disease.

Sidney Strickland, PhD

The Rockefeller University

Sidney Strickland is Professor and Dean of the Graduate School at The Rockefeller University in New York City. He received his BS in chemistry in 1968 from Rhodes College in Memphis. He obtained his PhD in biochemistry from the University of Michigan in 1972 where he studied the biophysics of enzymology with Vincent Massey. He then was a postdoctoral fellow for two years at Rockefeller with Edward Reich, where he initiated his work on plasminogen activators. He joined the faculty of Rockefeller as an Assistant Professor and then Associate Professor. In 1983, he accepted a position as Leading Professor at the State University of New York at Stony Brook. He returned to Rockefeller in 2000 and established the Laboratory of Neurobiology and Genetics. His lab studies mechanisms of neurodegeneration.

Cheryl Wellington, PhD

University of British Columbia

Dr. Wellington obtained her PhD in Microbiology at the University of British Columbia in 1991 and did postdoctoral training at Harvard Medical School, the University of Calgary, and the University of British Columbia. She joined the Department of Pathology and Laboratory Medicine at the University of British Columbia in 2000 and was promoted to Associate Professor in 2006.

Dr. Wellington’s research interests encompass include lipid and lipoprotein metabolism in the brain and how this relates to chronic and acute neurological disorders. Dr. Wellington’s group has made key contributions to the understanding of the role of apolipoprotein E (apoE) in Alzheimer’s Disease. ApoE is the major cholesterol carrier in the brain and the best established genetic risk factor for late-onset Alzheimer’s Disease. However, the mechanisms by which apoE affects Alzheimer’s Disease pathogenesis is poorly understood. Dr. Wellington’s laboratory has shown that the amount of lipids carried on apoE affects the metabolism of Aß peptides, which are toxic species that accumulate as amyloid plaques in the brains of patients with Alzheimer’s Disease and also accumulate in individuals who have suffered traumatic brain injury. Specifically, Dr. Wellington has identified the cholesterol transporter ABCA1 as the physiological transporter of lipids onto brain apoE. Her group has shown that mice deficient in ABCA1 have poorly-lipidated apoE in the brain and develop more amyloid, whereas transgenic mice that overexpress ABCA1 have lipid-rich apoE and have virtually no amyloid deposits. Her current research projects are aimed at developing methods to increase apoE lipidation in the brain for application to both Alzheimer's Disease and traumatic brain injury.

Abstracts

Vascular Contributions to Cognitive Impairment and Dementia
Philip B. Gorelick, MD, MPH, Hauenstein Neuroscience Institute

We carried out a systematic literature review to develop a guide for practitioners to gain a better understanding of vascular cognitive impairment (VCI), vascular contributions to cognitive impairment and dementia, and the potential for prevention and treatment of VCI or related cognitively impairing disorders of later life [1]. In this presentation we will primarily review cardiovascular risk markers for VCI and the prospects for prevention or slowing of cognitively impairing conditions of later life based on treatment or prevention of these factors. The discovery that certain cardiovascular factors are now considered risk markers for Alzheimer's disease (AD) has provided a new potential avenue for the prevention or treatment of AD. Thus, in addition to vascular amyloid, a focus of AD prevention and treatment may be the interface between traditional cardiovascular risk factors and the neurovascular unit. The complex interplay between vascular and AD pathologies in the evolution of clinically manifest VCI and AD must be kept in mind, and long-term vascular risk marker interventional studies beginning as early as midlife may be required to prevent or postpone these disorders.
 
1. Gorelick PB, Scuteri A, Black SE, Decarli C, Greenberg SM, Iadecola C, et al. Vascular contributions to cognitive impairment and dementia: A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011; 42: 2672–2713.
 

The Overlap between Neurodegenerative and Vascular Factors in Dementia
Costantino Iadecola, MD, Weill Cornell Medical College

The brain is uniquely dependent on a well-regulated delivery of oxygen and glucose through the blood supply. If the delivery of cerebral blood flow is not adequate to match the dynamic energetic requirements imposed by neural activity, brain dysfunction and damage ensues. There is increasing evidence that alterations in cerebral blood flow play a role not only in vascular causes of cognitive impairment, but also in Alzheimer's disease (AD). Vascular risk factors and AD impair the structure and function of cerebral blood vessels and associated cells (neurovascular unit), effects mediated by vascular oxidative stress and inflammation. Thus suppression of the major source of radicals in mice overexpressing the amyloid precursor protein (APP) ameliorates the cerebrovascular dysfunction and the attendant cognitive deficits. Injury to the neurovascular unit alters cerebral blood flow regulation, depletes vascular reserves, disrupts the blood-brain barrier and reduces the brain's repair potential, effects that amplify the brain dysfunction and damage exerted by incident ischemia and coexisting neurodegeneration. In support of this hypothesis occlusion of the middle cerebral artery in mice overexpressing APP leads to larger ischemic lesions, highlighting the reduced vascular reserves associated with cerebrovascular dysfunction. Clinical-pathological studies support the notion that vascular lesions aggravate the deleterious effects of AD pathology by reducing the threshold for cognitive impairment and accelerating the pace of the dementia. In addition, disturbances of cerebral perfusion and/or energy metabolism have also been observed early in the course of AD or even in non-demented subjects at genetic risk for AD. These observations, collectively, indicate that vascular alterations may be a contributing factor in the pathogenesis of AD. In the absence of mechanism-based approaches to counteract cognitive dysfunction in AD, targeting vascular risk factors and improving cerebrovascular health offers the opportunity to mitigate the impact of one of the most disabling human afflictions.
 

Gain-of-Function Somatic Mutations Initiate the Vascular Damage that Leads to Alzheimer's Dementia: A Hypothesis
Vincent Marchesi, MD, PhD, Yale School of Medicine

Alzheimer's dementia is the result of brain injury caused by oxidative damage, inflammatory reactions, and amyloid/abeta dysregulation. The late stages of this disease are well known, but the mechanisms that trigger this potentially lethal cascade are unknown and will have to be identified before rational approaches to prevention and treatment can be devised. The idea proposed here is that the human body, including the brain, is constantly exposed to reactive oxygens that have the potential to generate mutant proteins that provoke local inflammatory reactions and the accumulation of amyloid abeta peptides, creating conditions for localized ischemia, neuronal dysfunction, and eventually cell death. These non-germ line mutations result from ROS-induced miscoding of DNA and RNA that occur during one's lifetime and are distributed in mosaic patches throughout the body. It is proposed that these postulated proteins are products of genes and m-RNAs that code for activated forms of inflammasomes, such as NALP3 and cryopyrin, and mutant forms of the amyloid precursor protein (APP). Their identification could lead to novel diagnostic procedures and the development of new interventional therapies.
 

Understanding Cerebral Amyloid Angiopathy
Steven M. Greenberg, MD, PhD, Harvard Medical School

Cerebrovascular deposition of β-amyloid (cerebral amyloid angiopathy, CAA) is both a major cause of spontaneous hemorrhagic stroke in the elderly and an increasingly recognized contributor to vascular cognitive impairment (VCI). Although traditionally diagnosed post-mortem, CAA can now be identified during life by the neuroimaging presence of cortical microbleeds. The current presentation will focus on three rapidly developing features of CAA relevant to Alzheimer's disease and VCI: 1) detection of CAA via amyloid imaging, 2) CAA's effects on vascular function, and 3) the contribution of CAA to cerebral microinfarction. CAA's effects on vascular structure and physiology give it an important role in ongoing treatment approaches for both vascular and neurodegenerative forms of age-related cognitive impairment.
 

MRI Markers of Vascular Cognitive Impairment
Bruce R. Reed, PhD, UC Davis Alzheimer's Disease Research Center

It is well established that the major risk factors for cardiovascular disease are also risk factors for dementia in general and Alzheimer's disease (AD) specifically, as is the fact that the most common neuropathological substrate for dementia is a combination of ischemic vascular lesions and AD pathology. Our understanding of the exact role of vascular factors in the many intervening steps between risk, pathology and dementia is, however, quite incomplete. MRI is a method sensitive to the presence of vascular brain injury that can be used as an in vivo measure to help elucidate these relationships. This is especially so when MRI is combined with PIB PET to define the presence of AD pathology.
 
The traditional MRI markers of vascular brain injury identify infarcts and areas of altered white matter. Most models of vascular cognitive impairment emphasize a predilection of these lesions to occur in fronto-subcortical circuits with consequent cognitive executive deficits. In this talk I will present work from our laboratory that support the following points: 1) the concept of VBI should be extended to include cortical atrophy, which is a major driver of cognitive impairment in general. 2) the view that VBI causes executive dysfunction is overly simple, 3) the direct effects of VBI are most prominent and can be best differentiated from those of AD in non-demented persons, 4) VBI likely plays a very important role in MCI (and "normal" cognitive aging), independent of those of AD. These findings support an integrated model of vascular contributions to cognitive impairment that identifies VBI as having both focal and diffuse effects on brain and with cognitive consequences that change with the progression of the disorder and with comorbid AD.
 

The Effects of Abeta Immunotherapy on the Vasculature
Kejal Kantarci, MD, Mayo Clinic

Lowering Amyloid-β load with immunotherapy is the goal of many of the current clinical trials in Alzheimer's disease. The effects of active and passive immunization on the cerebral vasculature specifically in cases with cerebral amyloid angiopathy is an area of active research. MRI abnormalities associated with immunotherapy are recently classified into two subgroups: Amyloid-Related Imaging Abnormalities with vasogenic edema and sulcal effusions (ARIA-E) and microhemorrhages and hemosiderosis (ARIA-H). This presentation will focus on the possible pathophysiological mechanisms underlying ARIA-E and ARIA-H and the association between these imaging abnormalities and amyloid-β pathology in patients with Alzheimer's disease.
 

Hypertension, Cognitive Decline and Dementia: The Hidden Role of Obstructive Sleep Apnea
Gustavo C. Román, MD, Methodist Neurological Institute

Background: Hypertension has a deleterious effect on cognitive function particularly when midlife hypertension remains undiagnosed and untreated. The injury to the vascular system is manifested by ventricular enlargement, hypertensive retinopathy, renal damage, and brain injury from hemorrhagic and ischemic stroke. The primary alterations resulting from the physical effects of the increased intravascular pressure include endothelial damage, arteriolosclerosis, and atherosclerosis. Strokes, large and small, are the main cause of vascular cognitive impairment in hypertensive subjects. Onset of hypertension late in life causes added damage to a microvascular bed that has decreased in density and capacity for angiogenesis. Also, important is the decreased autoregulation of the elderly. These mechanisms increase the likelihood of cerebral hypoperfusion and hypoxemia leading to damage of distal and watershed territories manifested by ischemic demyelination of the white matter and lacunar strokes. Patients: We have recently observed in a group of consecutive elderly patients evaluated for cognitive decline at the Alzheimer and Dementia Clinic of the Methodist Neurological Institute (Houston, Texas). Polysomnography was performed in 106 patients for suspected obstructive sleep apnea (OSA) syndrome (history of snoring, nocturnal awakenings, and excessive daytime sleepiness).
 
Results: The mean age was 72.9 years; 51.5% men and 48.5% women. Mean Body Mass Index was 27.5 kg/m2 [range=19 – 41]. Most patients were Caucasian (59%), followed by Hispanics (25%), African Americans (12%) and Asian (4%). The main vascular risk factors were hypertension (77%), hypercholesterolemia (45%), cardiovascular disease (33%), diabetes (28%), and prior history of stroke (22%). A third of the cases had a family history of dementia. Clinical diagnoses of the cognitive problems included Mild Cognitive Impairment (MCI) Dysexecutive type (24%), Mixed Alzheimer's disease + Vascular Dementia (20%), MCI Amnestic type (17%), Vascular Dementia (12%), Alzheimer's disease (9%) and Normal Pressure Hydrocephalus (7%). MRI revealed extensive small vessel disease in 86% of the cases including lacunar strokes in the corona radiata and basal ganglia, as well as isolated white matter hyperintensities (34%). Large-vessel strokes were found in 17% of the cases. Severe OSA was found in 31% of the patients, moderate OSA in 47%, mild OSA in 19% and 4% had normal sleep.
 
Conclusion: OSA appears to be a significant factor in cognitive decline in the elderly, enhancing the effects of hypertension on small vessel disease in the brain.
 

TBI and AD: Vascular Coag-Inflammatory Pathways and Therapeutic Targets
Barry W. Festoff, MD, University of Kansas Medical Center and pHLOGISTIX LLC

Vascular, coagulation and inflammatory pathways converge in traumatic brain injury (TBI) and Alzheimer's disease (AD). Evolution has placed coagulation and innate immune cascades in close proximity to one another and they co-evolved to provide an advantage against invading pathogens. Procoagulants are proinflammatory and vice versa, namely that anti-coagulants are anti-inflammatory. The serine proteinase thrombin is a key player in both clotting and inflammatory pathways, the latter via cleavage activation of proteinase-activated receptors (PARs), which can be distinguished by PAR-specific agonist and antagonist peptides, PARAPs. The blood-brain barrier (BBB) becomes defective following TBI and is also involved in AD, where both amyloid Aβ and tau participate. Thrombin affects the BBB, as it does other barriers, inducing many endothelial cell (EC) responses that regulate hemostasis, thrombosis and vessel wall pathophysiology. One of these, EC intercellular gap formation and vascular permeability is a cardinal feature of inflammation and is regulated by an EC proteoglycan, thrombomodulin (TM). Understanding and controlling thrombin's influences may be an important therapeutic target in both TBI and AD. Aspects of thrombin inflammatory signaling up- and downstream of PARs in the brain by TM are a major focus of pHLOGISTIX. TM has another target, HMGB1, separate from thrombin, that is also prominent in TBI, BBB disruption, and possibly AD as well. In this discussion we approach this via in vitro and in vivo experiments.
 

Leukocyte Plugging of Capillaries Reduces Brain Blood Flow in Mouse Models of Alzheimer's Disease
Chris B. Schaffer, PhD, Cornell University

Alzheimer's disease (AD) is characterized by aggregates of amyloid-beta, which eventually accumulates into dense plaques scattered throughout the brain. Clinical research and experimental work suggest that cerebral blood flow is impaired in AD, although the mechanisms involved are not fully elucidated. We used in vivo two-photon excited fluorescence microscopy to examine cortical blood flow in aged mouse models of AD in an effort to identify mechanisms for impaired cortical blood flow. We found that the fraction of capillaries that are not flowing in AD mice (median of 2%) is greatly elevated as compared to age-matched wild-type animals (median of 0%). We further determined that these capillary stalls are caused by monocytes that are firmly stuck in individual capillary segments, suggesting an inflammation mediated mechanism. Because a single stalled capillary will impact the blood flow in downstream vessels, we estimate that this phenomena could lead to blood flow decreases of ~20%, potentially contributing to cognitive dysfunction in AD and reducing clearance of amyloid-beta from the brain.
 

Fibrinogen and β-amyloid Association Alters Thrombosis and Fibrinolysis: A Possible Contributing Factor to Alzheimer's Disease
Sidney Strickland, PhD, The Rockefeller University

Alzheimer's disease (AD) is a neurodegenerative disorder in which vascular pathology plays an important role. Since the β-amyloid peptide (Aβ) is a critical factor in this disease, we examined its relationship to fibrin clot formation in AD. In vitro and in vivo experiments showed that fibrin clots formed in the presence of Aβ are structurally abnormal and resistant to degradation. Fibrin(ogen) was observed in blood vessels positive for amyloid in mouse and human AD samples, and intravital brain imaging of clot formation and dissolution revealed abnormal thrombosis and fibrinolysis in AD mice. Moreover, depletion of fibrinogen lessened cerebral amyloid angiopathy pathology and reduced cognitive impairment in AD mice. These experiments suggest that one important contribution of Aβ to AD is via its effects on fibrin clots, implicating fibrin(ogen) as a potential critical factor in this disease.
 

Guarding Vascular Health with High Density Lipoproteins
Cheryl Wellington, PhD, University of British Columbia

High-density lipoprotein (HDL) is the principal facilitator of reverse cholesterol transport, a critical pathway of lipid metabolism whereby excess cholesterol is mobilized from peripheral tissues and delivered to the liver and steroidogenic organs for catabolism/removal and utilization. High levels of HDL-cholesterol (HDL-C) are consistently associated with reduced risk of coronary artery disease, atherosclerosis and cardiovascular events. ApoA-I, which comprises approximately 70% of the protein content of HDL, promotes cholesterol efflux via the lipid transporter ABCA1. Although apoA-I is not synthesized by glia or neurons, it is present in cerebrospinal fluid (CSF) at levels comparable to CSF apoE, which translates to approximately 0.1-0.5% of plasma apoA-I levels. In CSF, apoA-I- and apoE are on distinct lipoprotein particles. CNS apoA-I is believed to originate from two potential sources; secretion of apoA-I from cerebral vascular endothelial cells and/or translocation of plasma apoA-I across the blood brain barrier. Emerging evidence supports the involvement of apoA-I in maintaining cognitive and cerebrovascular health. Human epidemiological studies suggest that low levels of plasma HDL-C, especially in midlife, are associated with increased AD risk. Furthermore, AD mice that lack apoA-I have impaired spatial learning and elevated cerebrovascular amyloid deposition, whereas transgenic over-expression of apoA-I protects from age-associated learning and memory deficits and selectively decrease cerebrovascular amyloid load. These observations demonstrate a key role for apoA-I in regulating cerebrovascular amyloid metabolism. HDL also exerts direct anti-inflammatory and anti-thrombotic effects, stimulates nitric oxide synthesis, and promotes endothelial repair by enhancing the mobilization of endothelial progenitor cells. Despite this plethora of beneficial effects in cardiovascular medicine, the association of HDL with human AD remains poorly understood. This is due in part to limitations in study design, the profound heterogeneity of HDL particles, and the relatively poor association of HDL-C levels with HDL function. We have developed an indirect measure of HDL's cholesterol efflux capacity that is based on the rate at which a patient's circulating HDL particles can generate substrate for the cholesterol transporter ABCA1. Our assay can be used as an index of HDL's efflux capacity that is predictive of clinical states, including atherosclerosis, diabetes, and obesity. I will discuss the potential applicability of this novel assay of HDL function for AD.
 

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212.232.7700

Wall Street Inn

212.747.1500

Ritz-Carlton New York, Battery Park

212.344.0800