Therapeutics for Cognitive Aging

Therapeutics for Cognitive Aging

Friday, May 15, 2009

The New York Academy of Sciences

Presented By

Presented by The Alzheimer's Drug Discovery Foundation and The New York Academy of Sciences

 

This 1-day symposium will focus on an issue of great importance to an aging society – the development of novel therapies for cognitive decline across the lifespan of humans. This meeting will convene prominent basic and clinical scientists who study the cognitive and neurobiological aspects of aging and its consequences for cognition.

Speakers will cover three main areas:

  1. The definition of Cognitive Aging
  2. The underlying neurobiology of Cognitive Aging
  3. Issues in the development of potential new therapies for Cognitive Aging including the use of biomarkers, drug therapy and a discussion of related regulatory issues.

Agenda


7:45 AM

Registration & Continental Breakfast

8:30 AM

Welcome and Opening Remarks
Howard Fillit, MD, Executive Director, Alzheimer’s Drug Discovery Foundation

I. Defining Cognitive Aging

8:45 AM

What is Cognitive Aging?
Timothy A. Salthouse, PhD, University of Virginia

9:10 AM

Syndromal View: Day-to-Day Functional & Practical Implications of Cognitive Aging
Steven Ferris, PhD, New York University of Medicine

9:35 AM

Medical Co-morbidities and Lifestyle Risks for Cognitive Decline with Aging
Lenore J. Launer, PhD, National Institute on Aging

10:00 AM

Panel

10:30 AM

Break

II. Neurobiology of Cognitive Aging

11:00 AM

Anatomy and Pathology of the Aging Brain
Patrick Hof, M.D. Mount Sinai School of Medicine

11:25 AM

Myelin and Processing Speed With Aging
George Bartzokis, MD, University of California, Los Angeles

11:50 AM

Phosphodiesterase Inhibitors as a Mechanism for Enhancing Synaptic Plasticity
Robin Kleiman, PhD, Pfizer, Inc, Pfizer Global Research and DeveloPMent

12:15 PM

Neurochemical and Neuro-endocrine Changes with Aging
Victoria Luine, PhD, Hunter College

12:40 PM

Panel

1:10 PM

Lunch

III. Therapeutics

2:15 PM

Novel Therapeutics for Cognitive Aging
Jerry J. Buccafusco, PhD, Medical College of Georgia

2:40 PM

Biomarkers of Cognitive Aging
Gary W. Small, MD, University of California, Los Angeles

3:05 PM

Clinical Trial Design for Cognitive Aging Therapeutics
Paul S. Aisen, MD, University of California, San Diego

3:30 PM

Break

4:00 PM

Industry Perspective on Cognitive Aging Therapeutics
David Lowe, PhD, Memory Pharmaceuticals Corp.

4:25 PM

Regulatory Perspective
Allan Green, MD, PhD, JD, Allan M. Green, Esq., LLC

4:50 PM

Panel

5:20 PM

Closing Remarks
Howard Fillit, MD, Executive Director, ADDF

Organizer

Howard Fillit

Alzheimer's Drug Discovery Foundation

Fillit a geriatrician and neuroscientist, is the founding Executive Director of the Institute for the Study of Aging (ISOA), an Estée Lauder family foundation founded in 1998, and the Alzheimer’s Drug Discovery Foundation (ADDF), an affiliated public charity founded in 2004. ISOA and ADDF share a common mission of accelerating drug discovery for Alzheimer’s disease through venture philanthropy. Fillit was previously the Corporate Medical Director for Medicare at NYLCare Health Plans (acquired by Aetna, Inc. in 1998), responsible for over 125,000 Medicare members in several regional markets. He has had a distinguished academic medicine career, previously at The Rockefeller University, and currently at The Mount Sinai School of Medicine where he is a clinical professor of geriatrics and medicine and professor of neurobiology. He is the author or co-author of more than 250 scientific and clinical publications, and has received several awards and honors including the Rita Hayworth Award for Lifetime Achievement from the Alzheimer’s Association. He also serves as a consultant to pharmaceutical and biotechnology companies, health care organizations and philanthropies.

Speakers

Paul S. Aisen

University of California, San Diego

Aisen is professor of neurosciences at the University of California, San Diego. His primary research interest is the development of new treatment strategies for Alzheimer’s disease. After graduating from Harvard College, Aisen received his medical degree from the Columbia University College of Physicians and Surgeons in 1979 and pursued his clinical training as a resident in the Department of Medicine at the University Hospitals of Cleveland, and in the Department of Medicine at the The Mount Sinai Hospital in New York. He completed his Fellowship in the Division of Rheumatology at the New York University Medical Center before returning to The Mount Sinai Hospital as Chief Resident in the Department of Medicine. Aisen is a diplomate of the American Board of Internal Medicine, with specialty certification in Rheumatology and Geriatric Medicine. Aisen is currently directing a number of National Institute of Health (NIH)-funded multicenter therapeutic trials, and collaborates extensively with the pharmaceutical industry. He is Director of the Alzheimer’s Disease Cooperative Study, a consortium funded by the National Institute on Aging to develop assessment instruments and conduct clinical trials.

George Bartzokis

University of California, Los Angeles

Bartzokis is professor of psychiatry at UCLA. He has a long-standing interest in using brain imaging to assess the lifelong process of brain development and degeneration, and the relationship of these processes to neuropsychiatric diseases of development (such as schizophrenia and bipolar disorder) as well as degeneration (such as Alzheimer's disease). He helped develop a novel conceptualization of the human brain that focuses on myelin (the myelin model) and proposes that the development, maintenance, and degeneration of myelin contribute to many prevalent developmental and degenerative diseases that plague our species across the lifespan. His ultimate goal is to use brain imaging, genetic, and cognitive biomarkers to better define healthy brain processes and identify derangements at very early stages when treatment interventions can arrest and possibly reverse disease progression trajectories.

Jerry J. Buccafusco

Medical College of Georgia

Buccafusco is Regents’ Professor and Director of the Alzheimer’s Research Center, in the Department of Pharmacology and Toxicology of the Medical College of Georgia. He is also professor of psychiatry and health behavior. He holds a joint appointment as research pharmacologist at the Department of Veterans Affairs Medical Center. Buccafusco is also President and CEO (and founder) of Prime Behavior Testing Laboratories, Inc., (Evans, GA) a contract research company for the preclinical evaluation of cognition-enhancing therapeutic agents. Buccafusco has authored over 200 research publications and book chapters. His research area includes the development of novel treatment modalities for Alzheimer’s disease and related disorders. In 1988 his laboratory was the first to report the cognitive enhancing action of low doses of nicotine in non-human primates. Since that time he has studied numerous novel memory-enhancing agents derived from several pharmacological classes in this model. Most recently his laboratory is investigating the role of the immune system and in the production of auto-antibodies to βamyloid and to the receptor for advanced glycation end products (RAGE) by individuals with Alzheimer’s disease. These studies have been supported by continuous federally-sponsored grants and by several private foundations and commercial interests.

Steven Ferris

New York University

Allan Green

Allan M. Green, Esq., LLC

Patrick Hof

Mount Sinai School of Medicine

Hof is professor of neuroscience, geriatrics, and ophthalmology, the Regenstreif Professor of Neuroscience, the vice-chair of the Department of Neuroscience, and the director of the Kastor Neurobiology of Aging Laboratories at the Mount Sinai School of Medicine. Hof earned his MD from the University of Geneva School of Medicine, Switzerland. He came to the USA as a postgraduate fellow at the Research Institute of Scripps Clinic, La Jolla, CA. In 1989 he came to Mount Sinai School of Medicine as a Senior Research Associate. Hof's research is directed towards the study of selective neuronal vulnerability in dementing illnesses and aging using classical neuropathologic as well as modern quantitative morphologic methods to determine the cellular features that render the human brain uniquely vulnerable to degenerative disorders. Hof also conducts analyses of the distribution and connectivity patterns of pyramidal neuron subpopulations in the macaque monkey cerebral cortex in young and very old animals to study possible age-related changes in the neurochemical characteristics of the neurons of origin of corticocortical projections. He also develops morphometric, magnetic resonance microscopy, and stereologic tools for the study of neuroanatomical specimens and brain atlas development. Among his major contributions, Hof demonstrated specific neurons are selectively vulnerable in dementing disorders such as Alzheimer’s disease. He has made contributions to quantifying the differences between normal aging brains and Alzheimer’s disease, as well as other mental illnesses such as schizophrenia and autism. Hof is also the curator of a mammalian brain collection that includes a large series of great ape specimens, as well as and extensive sample of marine mammals. He has contributed considerably to our understanding of the structure of the cetacean brain and has discovered neuronal types unique to whales and hominids.

Robin Kleiman

Pfizer, Inc, Pfizer Global Research and Development

Kleiman is a senior principal scientist in the psychosis target identification and validation unit at Pfizer, Inc. Kleiman received her PhD in Neuroscience from the University of Virginia while working with Oswald Steward. Her thesis work focused on understanding mechanisms of dendritic RNA sorting and transport in cultured neurons. Her post-doctoral work at the University of California San Francisco, in the laboratories of Zach Hall and then Louis Reichardt examined receptor tyrosine kinase signal transduction, neurite outgrowth and neurotrophin-induced synaptic plasticity at the neuromuscular junction. Kleiman joined the CNS Discovery Biology group at Pfizer, Inc. in 1999. Since joining Pfizer, her laboratory group has been involved in generating novel assays and functional screens using image-based platforms for high content screening and development of functional genomics strategies for new target identification in Neurodegeneration and Psychotherapeutics. Kleiman began working with the CNS phosphodiesterase group in 2001 and has developed a particular interest in the therapeutic utility of these enzymes in Neurodegenerative and Psychiatric diseases.

Leonore J. Launer

National Institute on Aging

Launer is Chief of the Neuroepidemiology Section, Laboratory of Epidemiology, Demography and Biometry, National Institute on Aging. She is an internationally recognized neuro-epidemiologist who has a long history of international collaborations. Her main research interests are in the metabolic, inflammatory, vascular and genetic factors that interact and lead to pathologic brain aging and function. She is a Principal Investigator on the Age Gene Environment Susceptibility – Reykjavik Study, is PI of the “Action to Control Cardiovascular Risk in Diabetes” – Memory in Diabetes trial investigating the effects on the brain of standard vs intensive treatment of cardio-vascular risk factors, and collaborates closely on the Honolulu Asia Aging Study.

David Lowe

Memory Pharmaceuticals Corp.

Victoria Luine

Hunter College

Timothy A. Salthouse

University of Virginia

Salthouse is Brown-Forman Professor of Psychology at the University of Virginia. Salthouse’s research explores the changes in cognitive functioning over the life-span and the mechanisms responsible for the decline in cognitive functioning as a result of aging. He has been internationally recognized for his work on cognitive aging and has published 9 books and over 200 chapters and journal articles.

Gary W. Small

University of California, Los Angeles

Small is professor of psychiatry and biobehavioral sciences and the Director of the UCLA Center on Aging. He has developed new brain-imaging technology that allows physicians to detect brain aging and Alzheimer's disease years before patients show symptoms. Small has authored over 500 scientific publications, received numerous awards, and written four popular books (The Memory Bible, The Memory Prescription, The Longevity Bible, and iBrain).

Clinical Trial Design for Cognitive Aging Therapeutics

Paul S. Aisen, MD, University of California, San Diego

The development of therapeutics for cognitive aging poses significant difficulties. One or more primary outcome measures that capture the range of age-related cognitive change and have sensitivity to therapeutic effects must be selected or designed and validated; the heterogeneity of cognitive abilities will be a significant barrier to be overcome. A global or functional measure will likely be required to establish the clinical importance of any measured change in cognition. If a therapeutic agent is expected to slow decline rather than enhance cognition, large and lengthy trials will be necessary to demonstrate efficacy.

Myelin and Processing Speed with Aging

George Bartzokis, MD,University of California, Los Angeles

Myelination of the human brain results in roughly quadratic trajectories of myelin content and integrity, reaching a maximum in mid-life and then declining in older age. This trajectory is most evident in vulnerable later-myelinating association regions such as frontal lobes, it is influenced by apolipoprotein genotype, and it may be the biological substrate for similar lifespan trajectories of cognitive processing speed and motor speed. Brain functions that depend on speed of action potential propagation and high-frequency bursts of action potentials should be especially vulnerable to the aging-related process of myelin breakdown. Non-invasive measures of myelin integrity together with testing of basic measures of processing speed may aid in developing and targeting anti-aging treatments to mitigate inevitable age-related cognitive declines that proceed the development of highly-prevalent age-related dementing disorders such as Alzheimer's disease.

Novel Therapeutics for Cognitive Aging

Jerry Buccafusco, PhD, Medical College of Georgia

The marked decline in FDA-approved new drug candidates in recent years suggests the possibility that the “low-hanging fruit” has mostly been harvested. This might be particularly applicable to drugs acting on the central nervous system. Fortunately, there are several examples for the utility of multi-functional drugs - compounds or drug mixtures that act on multiple additive or synergistic targets. The expectation is that single target molecules with high specificity might not have access to complex interacting neural pathways; and that moderate potency could engender fewer off-target side effects. Multi-functional compounds might be designed with the ability to (1) offer both palliative and disease modifying actions; (2) act on targets that produce additive or synergistic therapeutic responses; (3) simultaneously evoke a therapeutic response at the desired target and prevent an undesired response mediated by an alternate target; (4) allow one component to promote the drugable characteristics (e.g., brain penetration) of the therapeutic component; and (5) prolong the duration of effectiveness of one compound by contributing the pharmacodynamic actions of another. The author takes the liberty to include in the presentation examples of the above situations from studies in his laboratory.

Anatomy and Pathology of the Aging Brain

Patrick Hof, MD, Mount Sinai Medical Center

The human brain is uniquely powerful with respect to cognitive abilities, yet the hippocampal and neocortical circuits that mediate such complex functions are highly vulnerable to aging. Their selective vulnerability is profoundly manifested in Alzheimer's disease (AD), where degeneration of select neurons leads to a near complete loss of cognitive abilities. We will review aspects of age-related neuropathology and present evidence about neuronal selective vulnerability in age-associated cognitive impairment - a decline in cognitive status presenting as deficits in memory and key capacities for strategic use of acquired information. Animal studies suggest that both AD and age-associated cognitive impairment reflect vulnerability of the same circuits. However, neuron death predominates in the former, whereas the latter is probably mediated by synaptic alterations in otherwise intact circuits which could be candidate for therapeutic interventions aimed at restoring or maintaining function.

Phosphodiesterase Inhibitors as a Mechanism for Enhancing Synaptic Plasticity

Robin Kleiman, PhD, Pfizer, Inc, Pfizer Global Research and Development

This presentation will review literature and gene chip data suggesting synaptic plasticity and associated signaling cascades are differentially altered in aging and disease. I will describe the role of phosphodiesterase enzymes in sculpting the temporal and spatial dynamics of cyclic nucleotide signaling events involved synaptic plasticity, with a particular emphasis on the differential regulation of gene expression produced by specific phosphodiesterase inhibitors within pathways associated with synaptic plasticity.

Medical Co-morbidities and Lifestyle Risks for Cognitive Decline with Aging

Leonore J. Launer, PhD, National Institute on Aging

It is becoming increasingly evident that several highly prevalent sub-clinical and clinical cardio-vascular risk factors contribute to the decrements in cognitive function that are observed with aging. This presentation will review data on these factors, with a focus on diabetes and hypertension. The factors will also be examined in the context of age related changes in both risk factors and cognitive function.

Biomarkers of Cognitive Aging

Gary W. Small, MD, University of California, Los Angeles

Technological advances have led to several strategies for measuring the biological manifestations of cognitive aging. Structural imaging, particularly magnetic resonance imaging measures of regional atrophy, can identity people with mild symptoms that are likely to progress. Such functional methods as positron emission tomography scanning of glucose metabolism can also demonstrate regional declines that predict subsequent neurodegeneration. New neuroimaging methods in development can measure specific neurotransmitter systems, amyloid plaque and tau tangle concentrations, and neuronal integrity and connectivity. Measures of amyloid-beta, tau and other markers in cerebrospinal fluid and serum have been useful in identifying and tracking patients with varying degrees of cognitive aging. Successful co-development of such biomarkers and prevention treatments may eventually lead to a combination of tests or “biosignature” that determines the risk for rapid cognitive aging, which might be used to monitor disease-modifying medications, vaccines, or other interventions designed to reduce the risk of future cognitive losses and delay onset of disease.

What is Cognitive Aging?

Timothy A. Salthouse, PhD, University of Virginia

This presentation will provide an overview of the nature of cognitive aging in healthy normal populations. The discussion will cover the types of cognitive variables that are and are not related to age, the nature of the age trends in cross-sectional and longitudinal comparisons, and some of the hypotheses that have been proposed to account for the relations between age and measures of cognitive functioning.

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