Cosponsors: National Institute of Mental Health's Office of Research on Women's Health and The Alzheimer's Association
Workshop Moderator: Dr. Bruce McEwen
Workshop Objectives
The objectives of this workshop were to:
- Define and examine the discrepancies between the findings of the Women's Health Initiative on brain and cognitive function and the basic and longitudinal/epidemiological studies including different formulations, doses, duration of treatment, timing, and mode of administration.
- Examine the effects of estrogens on brain and cognitive function as they relate to aging.
- Determine what is known and what information is needed that would determine whether additional hormone “interventions” could be developed.
- Determine the lessons learned from studies on estrogen that will help in designing clinical trials for other classes of drugs.
Tuesday, September 28, 2004: Day 1
8:00 a.m.–8:10 a.m. Introductory Remarks
Dr. Marcelle Morrison-Bogorad
Meeting Logistics and Statement of Conflicts of Interest
Dr. M. Miller
8:10 a.m.–8:30 a.m. Welcome
Dr. Bruce McEwen
Abstract Presentation in Adobe PDF (3.14M)
I. Basic Science: Effects of Estrogen and Progesterone on CNS Cellular Systems and in Animal Models
Moderator: Dr. Bruce McEwen
A. Neurobiology of Estrogen and Progesterone
8:30 a.m.–9:00 a.m.
Estrogen Mechanisms of Action in Neurons: Factors That Determine Outcome In Vitro as Predictors of Efficacy In Vivo
Dr. Roberta Brinton
Abstract Presentation in Adobe PDF (395K)
9:00 a.m.–9:20 a.m.
In Defense of Estradiol and Progesterone
Dr. Dominique Toran-Allerand
Abstract Presentation in Adobe PDF (850K)
9:20 a.m.–9:35 a.m.
Audience Discussion
B. Cognitive Function: Age-Related Changes in Estrogen/Progesterone Levels and Cognitive Function
9:35 a.m.–9:50 a.m.
Hormone Therapy and Cognitive Performance: Reconciling Animal Studies With Clinical Data
Dr. Robert Gibbs
Abstract Presentation in Adobe PDF (1.62M)
9:50 a.m.–10:05 a.m.
Estrogen Influences on Cognitive Aging in Monkeys
Dr. Peter Rapp
Abstract Presentation in Adobe PDF (1.14M)
10:05 a.m.–10:15 a.m. BREAK
10:15 a.m.–10:30 a.m.
Estrogen and the Aging Cortical Synapse: Implications for Cognitive Effects in Aged Monkeys
Dr. John Morrison
Abstract Presentation in Adobe PDF (922K)
10:30 a.m.–10:45 a.m.
Panel and Discussion
Leader: Dr. MaryLou Voytko
Presentation in Adobe PDF (148K)
10:45 a.m.–10:55 a.m. Wrapup
Dr. MaryLou Voytko
C. Neuroprotection: Summary of Data That Estrogen/Progesterone Are or Are Not Neuroprotective
10:55 a.m.–11:10 a.m.
Role of Nonfeminizing Estrogens in Brain Protection From Cerebral Ischemia: An Animal Model of Alzheimer's Disease Neuropathology
Dr. James Simpkins
Abstract Presentation in Adobe PDF (1.94M)
11:10 a.m.–11:25 a.m.
Ovarian Steroids, Neuroinflammatory Responses, and Aging
Dr. Caleb Finch
Abstract Presentation in Adobe PDF (1.85M)
11:25 a.m.–11:50 a.m.
Discussion
Leader: Dr. Roberta Brinton
11:50 a.m.–12:05 p.m.
Broad Discussion on the Morning's Topics With Audience Participation
Leader: Dr. Bruce McEwen
12:05 p.m.–12:15 p.m. Wrapup of the Morning Session
Dr. Bruce McEwen
12:15 p.m.–1:15 p.m. LUNCH
II. Clinical Studies
Moderator: Dr. Claudia Kawas
1:15 p.m.–1:30 p.m.
Cardiovascular Health and Cognition: Perspectives on Using the Primate as a Model for Human Research
Dr. Thomas B. Clarkson
Abstract Presentation in Adobe PDF (368K)
1:30 p.m.–1:45 p.m.
Consequences of Surgical Menopause on Cognition and Mood
Dr. Barbara Sherwin
Abstract Presentation in Adobe PDF (810K)
1:45 p.m.–2:00 p.m.
CNS Effects of Hypogonadism and Estrogen Therapy in Humans
Dr. Peter Schmidt
Abstract Presentation in Adobe PDF (608K)
2:00 p.m.–2:15 p.m.
The Differential Effects of Estrogen on Mood and Cognition in Peri- and Postmenopausal Women
Dr. Neill Epperson
Abstract
2:15 p.m.–2:30 p.m.
Estrogen or no Estrogen: Long-Term Followup
Dr. Natalie Rasgon
Abstract Presentation in Adobe PDF (686K)
2:30 p.m.–2:45 p.m.
Low Dose Estrogen, fMRI, and Cognitive Function
Dr. Vincent P. Clark
Abstract Presentation in Adobe PDF (556K)
2:45 p.m.–3:00 p.m.
Cognitive and Brain Aging: Using Imaging To Distinguish Potential Risks and Benefits of Estrogen
Dr. Susan Resnick
Abstract Presentation in Adobe PDF (1.18M)
3:00 p.m.–3:25 p.m.
Vascular Disease in the Brain: An Important Cause of Dementia?
Dr. Lew Kuller
Abstract Presentation 1 in Adobe PDF (1.73M); Presentation 2 in Adobe PDF (967K)
3:25 p.m.–3:40 p.m. Audience Discussion and Wrapup
Dr. Claudia Kawas
3:40 p.m.–3:55 p.m. BREAK
III. Longitudinal and Epidemiological Studies
3:55 p.m.–4:10 p.m.
Levels of Endogenous Sex Steroids and Risk for Brain Aging
Dr. Lenore Launer
Abstract Presentation in Adobe PDF (316K)
4:10 p.m.–4:25 p.m.
Estrogen Therapy and Risk of AD in the Baltimore Longitudinal Study of Aging
Dr. Claudia Kawas
Abstract Presentation in Adobe PDF (303K)
4:25 p.m.–4:40 p.m.
A Population-Based Longitudinal Study of Cognitive Functioning in the Menopausal Transition (SWAN)
Dr. Peter Meyer
Abstract Presentation in Adobe PDF (313K)
4:40 p.m.–4:55 p.m.
Estrogen Exposures in Midlife, Memory, and Dementia
Dr. Victor Henderson
Abstract Presentation in Adobe PDF (204K)
4:55 p.m.–5:10 p.m.
Are Epidemiologic Studies Worthless as an Indication of Trial Results, or Does “Nixon's Law” (Timing Is Everything) Prevail?
Dr. John Breitner
Abstract Presentation in Adobe PDF (276K)
5:10 p.m.–5:25 p.m.
Methodologic Challenges in the Nonexperimental Study of Hormones and Dementia
Dr. Diana Petitti
Abstract Presentation in Adobe PDF (323K)
5:25 p.m.–5:45p.m. Panel and Audience Discussion
Leader: Dr. Claudia Kawas
5:45 p.m.–6:00 p.m. Wrapup
Dr. Bruce McEwen
Wednesday, September 29, 2004: Day 2
IV. CLINICAL TRIALS
Moderator: Dr. Leon Thal
8:00 a.m.–8:05 a.m. Introduction
Dr. Leon Thal
A. Prevention and Treatment Trials
8:05 a.m.–8:20 a.m.
Hormones and CHD: Discrepancies Between Laboratory Studies, Observational Studies, and Clinical Trials
Dr. Jacques Rossouw
Abstract Presentation in Adobe PDF (2.3M)
8:20 a.m.–8:40 a.m.
Design and Analysis of the Women's Health Initiative Memory Study (WHIMS)
Dr. Steve Rapp
Abstract Presentation in Adobe PDF (775K)
8:40 a.m.–9:00 a.m.
Implications of WHIMS
Dr. Sally Shumaker
Abstract Presentation in Adobe PDF (762K)
9:00 a.m.–9:15 a.m.
PREPARE: Preventing Postmenopausal Alzheimer's Disease with Replacement Estrogen
Dr. Mary Sano
Abstract Presentation in Adobe PDF (242K)
9:15 a.m.–9:30 a.m.
Results of the ADCS Estrogen Treatment Trial for AD
Dr. Ruth Mulnard
Abstract Presentation in Adobe PDF (320K)
9:30 a.m.–9:45 a.m.
Alzheimer's Disease: Efficacy of Transdermal 17 Beta-Estradiol
Dr. Sanjay Asthana
Abstract Presentation in Adobe PDF (2.53M)
B. SERMS and Cognition
9:45 a.m.–10:00 a.m.
The Effect of SERMs on Cognitive Function and Dementia
Dr. Kris Yaffe
Abstract Presentation in Adobe PDF (194K)
C. Design of Clinical Trials
10:00 a.m.–10:15 a.m.
Ethical Framework for the Design and Conduct of Clinical Trials
Dr. Frank Miller
Abstract Presentation in Adobe PDF (120K)
10:15 a.m.–10:30 a.m. BREAK
10:30 a.m.–10:50 a.m. Discussion: Clinical Trials
10:50 a.m.–11:05 a.m. Wrapup of Clinical Trials Session
Dr. Leon Thal
V. Where Do We Go From Here?
Moderator: Dr. Leon Thal
Discussion: Key Issues Concerning Estrogen Therapy—Design and Outcome
11:05 a.m.–11:35 a.m.
Design of Completed Studies
Are there examples of other clinical studies that did not follow the expectations provided by basic and epidemiological studies?
11:35 a.m.–12:05 p.m.
Design of Possible Future Studies
To guide us in the development of clinical trials, how can we use the information gained from the studies on estrogen to help us understand how to collect the most useful data from basic science and epidemiological studies?
Discussion Points for the Morning
- Age at start of treatment
- Immediate versus long-term effects
- Mode of treatment: transdermal versus oral
- Informative surrogate outcomes
- Mounting a full-scale clinical trial versus smaller clinical trials
- Physiology
- Timing of dosage
- Types of estrogen
- Duration of treatment
- Cyclic versus tonic
- Comorbidities
- With and without estrogen
- Progesterone and progestins
- Gender differences
- Choice of cohort
12:05 p.m.–1:00 p.m. LUNCH
1:00 p.m.–2:00 p.m.
Interfacing Basic and Clinical Science
How can basic scientists and clinicians better interact to help the findings in cellular, molecular, and basic studies be best used in the design of clinical trials?
Discussion Points for the Afternoon
- Do basic science models help in the clinical arena?
- Are in vitro studies and animal models needed?
- What's been answered in terms of discrepancies between basic science outcomes and clinical outcomes?
- Validity of cellular models
- Validity of animal models
- Distal effects
- Treatment
- Long-term treatment
- Event-driven, short-term treatment
- Do monkey studies better inform the design of clinical trials than studies on lower animals?
- Stage of disease versus no disease as a starting point
- Atherosclerosis
- Cognitive function
- Single-outcome studies versus multiple-outcome studies (e.g., cardiovascular/cognitive). How does basic science impact outcome in clinical trials?
- For brain-oriented studies in older animals: do not waste the tissue. What other organ systems can be examined in ongoing studies?
- What triggers pathological events in established lesions?
- Comparisons between basic science outcomes and clinical outcomes: valid or not?
- Issues of timing, dosage, route of administration, type of estrogen
- In addition to clinically significant changes in the course of disease, what are the goals of clinical estrogen research?
- Decreasing Alzheimer's disease risk
- Basic information on whether or how estrogen modulates brain function (cognition, etc.) without necessarily being clinically significant
2:00 p.m.–2:30 p.m. Tying It Together
Dr.Leon Thal
- What questions can be answered, and what cannot be answered in future clinical trials?
- Who might subjects be?
- What conditions can be recognized for exclusion from a study?
2:30 p.m.–2:45 p.m. Wrapup
Dr. Bruce McEwen
