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Council Minutes - May 2002

National Advisory Council on Aging

Summary Minutes: The Eighty-Sixth Meeting

May 21-22, 2002


CONTENTS

  1. Review of Applications
  2. Call to Order
  3. Report: Geriatrics and Clinical Gerontology Program Review
  4. Report: Task Force on Minority Aging Research
  5. Report: Working Group on Program and Clinical Investigators Working Group
  6. Program Highlights
  7. Adjournment
  8. Certification

Attachment A - Roster of the National Advisory Council on Aging
Attachment B - Director's Status Report

The 86th meeting of the National Advisory Council on Aging (NACA) was convened on Tuesday, May 21, 2002, at 3:00 p.m., in Building 31, Conference Room 6, National Institutes of Health (NIH), Bethesda, Maryland. Dr. Richard J. Hodes, Director, National Institute on Aging (NIA), presided.

In accordance with the provisions of Public Law 92-463, the meeting was closed to the public on Tuesday, May 21, from 3:00 to 5:00 p.m. for the review, discussion, and evaluation of grant applications in accordance with the provisions set forth in Sections 552(b)(c)(4) and 552(b)(c)(6), Title 5, U.S. Code, and Section 10(d) of Public Law 92-463. [1] The meeting was open to the public on Wednesday, May 22, from 8:00 a.m. to 1:30 p.m.

Council Participants:

Dr. Dennis Ausiello
Dr. John Cambier
Dr. Judith Campisi
Dr. Rose Dobrof
Dr. David Espino
Dr. Fred Gage
Dr. Mary Harper
Dr. Lewis Kuller
Dr. Stanley Prusiner
Ms. Judith Riggs
Dr. Ilene Siegler
Dr. Jeanne Wei
Dr. Myron Weisfeldt
Dr. Phyllis Wise

Ex-Officio Participants:

Dr. James Burris, (VA)
Dr. George Fuller
Dr. Don Grant (AoA)

Absent:

Dr. Dennis Selkoe
Dr. James Vaupel
Dr. David Wise

The Council Roster, which gives titles, affiliations, and terms of appointment, is appended to these minutes as Attachment A.

Members of the Public Present:

Ms. Nancy Aldrich, Aging Research & Training News
Dr. Stacey Fannon, Society for Women's Health Research
Ms. Linda Harootyan, Gerontological Society of America (GSA)
Ms. Jennifer Hedrick, PAA/APC
Dr. Rose Li, Analytical Sciences, Inc. (ASI)
Ms. Pam Moore, Capital Publications
Ms. Stephanie Reed, American Association for Geriatric Psychiatry
Dr. Carol Schutz, GSA
Ms. Joan Levy Zlotnik, Institute for Advancement of Social Work Research

In addition to NIA Staff, other Federal employees attending were:

Ms. Georgeanne Patmios, OD/OBSSR/NIH

  1. Review of Applications

This portion of the meeting was closed to the public in accordance with the determination that it was concerned with matters exempt from mandatory disclosure under Sections 552b(c)(4) and 552b(c)(6), Title 5, U.S. Code and Section 10(d) of the Federal Advisory Committee Act, as amended (5 U.S.C. Appendix). [2]

A total of 693 applications requesting $593,473,905 for all years underwent initial review. Council recommended 466 for a total of $431,970,126 for all years. The actual funding of the awards recommended is determined by the availability of funds, percentile ranks, priority scores, and program relevance.

  1. Call to Order

Dr. Hodes called the meeting to order at 8:00 a.m. on Wednesday, May 22, 2002, and welcomed members.

Director's Status Report

Dr. Hodes presented the Director's Status Report. He began with an overview of the ongoing appropriations process. Hearings have been held and the President's budget has been proposed. The President's budget request for NIA is $972 million, an 8.4 percent increase over FY 2002.

Dr. Hodes noted that the Task Force on Aging Research, in its 1995 report, recommended a budget of $1 billion for research on aging. The amount spent on aging research by NIA and other NIH institutes now exceeds that amount.

Budgetary trends indicate continued increases in the NIH budget. The NIH increase is approximately 15 percent and would complete the doubling of the budget proposed five years ago. A major portion of the 15 percent increase will be allocated to biodefense. For FY 2004 and beyond, it is projected that the increase will drop to 2 percent per year. All institutes are planning for that eventuality.

Although budget increases have been substantial in recent years, success rates have not increased dramatically. Dr. Hodes posited that the scientific community responds to increases rapidly by submitting more and larger applications.

Dr. Hodes presented the FY 2003 President's budget by mechanism. The distribution by mechanism is similar to recent years: almost 65 percent RPG, 2.2 percent SBIR, 8.7 percent Centers, 2.3 percent training, 5.4 percent contracts, 3.2 percent other mechanisms, 10 percent intramural research, and 3.5 percent research management and support.

Dr. Hodes updated the Council on the status of awards to new investigators. New investigators are defined as individuals who have not served as principal investigator on any PHS research project grants other than small grants, AREA , Planning Grants or Mentored Career Development Awards. NIH has been tracking awards to new investigators since the R29 award was discontinued in 1998. From 1997-2000, awards to new investigators have increased 10 percent NIH-wide and 20 percent for NIA. Most of the awards were to PhDs as compared to MDs and MD/PhD investigators. However, five years after an initial award, only 50 percent of those awards remain active (or 50 percent of PIs are funded). Data are not available on differential retention of awards by MD vs. PhD scientists. Dr. Hodes pointed out that the increase in new investigators was during the period of substantial NIH and NIA budget increases.

NIA has received 38 applications for the new NIH extramural loan repayment program. Dr. Hodes indicated that the Institute expects to fund a substantial portion of them. Current eligibility requirements include NIH support. Next year, NIH support will not be an eligibility requirement, and the budget allocation for loan repayment will double. Peer reviewers for the loan repayment applications were grantees with broad experience as mentors and in training programs. Review criteria, aside from eligibility, included an assessment of mentors, letters of recommendation, commitment to clinical research, and the applicants' potential as a clinical researcher. Council discussed the relative merits of assigning higher priority to those with a demonstrated track record of research versus those on the verge of making a decision to commit to a research career. Council members recommended that applicants be given clear feedback, including reasons for success or failure of their applications. They recommended also that financial burden be considered as an additional criterion after scientific review. Whether the loan repayment program will be evaluated was discussed. It was recommended that annual reports be requested from awardees and that their careers be tracked.

Council members were given a list of future meeting dates:

Future Meeting Dates

  • September 24-25, 2002 (Tuesday-Wednesday)
  • February 4-5, 2003(Tuesday-Wednesday)
  • May 20-21, 2003 (Tuesday-Wednesday)
  • September 23-24, 2003 (Tuesday-Wednesday)
  • February 3-4, 2004 (Tuesday-Wednesday)
  • May 24-25, 2004 (Monday-Tuesday)
  • September 23-23 2004 (Wednesday-Thursday)

Consideration of Minutes of Last Meeting

The Minutes of the January 2002 meeting were considered. A motion was made, seconded, and passed to approve the Minutes.

  1. Report: Geriatrics and Clinical Gerontology Program Review

Dr. Weisfeldt, chair of the Program Review Committee, reported to Council on the review of the Geriatrics and Clinical Gerontology (GCG) Program. Reviewers included four members of Council (Drs. Weisfeldt, Espino, Kuller, and Burris (ex officio)and three external scientists (Drs. Fried, Miller, and Reed). This was the first review of the new program structure: The Geriatrics Branch which deals with health issues of older persons and the Clinical Gerontology Branch that focuses on aging changes over the life span, and the Clinical Trials Branch that will manage and monitor medium and large scale clinical trials. The NIA website has a more detailed description of the new program structure (http://www.nia.nih.gov/research/extramural/geriatrics/). Reviewers applauded the change in structure from organ systems to broader areas.

The GCG program has a $100 million budget to support extramural projects. The Geriatrics Branch supports 138 grants, the Clinical Gerontology Branch 127 grants, and the newly established Clinical Trials Branch 23 grants.

Strengths of the program are the research it has stimulated on disease and organ systems, population diversity and health disparities, career development, and translational research. Program leadership, quality, and new structure also were considered strengths.

Reviewers raised some questions about Phase I and II trials of exercise and caloric restriction. They expressed concern that maintenance of weight reduction is unsuccessful. Therefore, interventions that are effective may not have promise or impact on long-term health and aging. It was pointed out that maintenance of weight reduction or adherence to exercise regimens is a behavioral issue and might profit from collaboration between the Behavioral and Social Reasearch (BSR) and GCG programs.

Reviewers considered that pharmacologic studies have greater impact over time than diet and exercise interventions. As an example, results of a recent clinical trial were cited that showed that in a sample randomized to treatment or placebo, regardless of LDL, treatment with statins resulted in a 25 percent reduction in stroke in older people.

Reviewers also focused on successful aging and recommended that the program support studies of whether the absence of risk factors for decline with age identify those who age successfully. They recommended that the program allocate resources to study the relation between early, midlife, and late life aging changes; and also, the extent to which common risk factors for decline may have a common biological basis. In a related recommendation reviewers proposed that the GCG program establish an assessment measure to track research progress in improving quality of life and extending longevity.

Reviewers advised the program to increase activity to foster public and professional education on health of older persons. In terms of research management, reviewers saw advantages to GCG working more closely both with the Behavioral and Social Research Program (BSR)—because of the role of behavioral choices in reducing disability—and with the Biology of Aging Program (BAP), to integrate basic and clinical research more closely in targeted areas such as repair of tissue injury. They noted that there is an interest in, and need for knowledge about, e.g., medication interactions, choice of medications, intensity and type of exercise appropriate for older persons, etc.

On training, reviewers recommended that NIA establish a data base to track trainees with special attention to MD investigators and to training programs for minority investigators.

Overall, reviewers were enthusiastic about the program, its leadership and staff, and with the program's use of resources.

  1. Report: Task Force on Minority Aging Research

Dr. Espino, chair of the Task Force, expressed the Task Force's interest and excitement in continuing the Summer Institute on Aging Research which has 42 participants.

He commented on the Resource Centers for Minority Aging Research (RCMARs) which are coming up for a second round or review. There are 22 applications, a number equal to the first solicitation and that signifies continuing interest in the field.

The Task Force reviewed the Institute of Medicine Report on unequal treatment confronting racial and ethnic minorities. They plan to study the report in concert with the Task Force-generated minority aging research strategic plan to see if they match up in terms of goals regarding issues of racial and ethnic disparities. The Task Force will discuss this at their next meeting.

At the request of a Council member, the issue of minority only initiatives will be discussed at the next meeting of the Task Force.

  1. Report: Working Group on Program and Clinical Investigators Working Group

Dr. Wise introduced the co-chairs of the Clinical Investigators Working Group, Dr. Ausiello and Dr. Prusiner, who summarized the major points made at the earlier meeting. Both specified the problem as the dramatic decline in new physician-investigators who develop research careers. Dr. Prusiner emphasized the contributions that physician-investigators can make, particularly to translational and patient-oriented disease-specific research. He indicated that lack of early research experience, lack of research mentoring, and indebtedness are responsible in large part for the decline.

Dr. Ausiello mentioned that a consensus had emerged that NIA should start to offer research training experiences earlier in medical school careers, including to medical students. He and Dr. Prusiner sought data from existing programs that provide support to medical students who seek a year off medical school to pursue research including the Doris Duke, Hartford, and Howard Hughes Foundations, and urged that the data on success and on how these programs are monitored be available to Council prior to the meeting in September. Dr. Prusiner also called for a day and half retreat, away from the Bethesda campus, to develop strategies to address the problem. He urged that the meeting occur between September 2002 and February 2003 with final decisions on initiatives to address the problem being made at the February 2003 meeting.

In discussion, Dr. Hodes acknowledged the guidance and leadership shown by Drs. Ausiello and Prusiner. He indicated that although he recognized that the problem is not one unique to NIA, nevertheless beginning with an Institute-specific initiative would allow faster development than working through NIH. He mentioned a second meeting being organized by Dr. Salerno, and due to occur in Summer 2002, that would offer an opportunity to collect much of the data being sought by Drs. Ausiello and Prusiner. He sought a core group of Council members who would work with Drs. Ausiello and Prusiner to develop the planned retreat and subsequent report. Drs. Weisfeldt, Kuller, and Dobrof agreed to participate.

Dr. Weisfeldt brought up another issue holding back the research careers of physicians. He called it the “over-regimenting” of credentialing of physicians. The difficulties of developing flexible physician-training that allows time out for research have become substantial. He suggested inviting the American Association of Medical Colleges (AAMC) to the retreat to gain the perspective of credentialing organizations. Dr. Hodes agreed with Dr. Weisfeldt's remark and commented that although funding agencies can help to address the problem, changes are needed at medical schools themselves to allow environments where young physicians can be supported and mentored to become scientists. Dr. Kuller urged that information on the careers of the few physicians who have succeeded in obtaining research grant support be sought. Are they pursuing translational research?

NIA staff reported on the recommendations for research developed by recent advisory meetings organized by NIA: the Human Biospecimen Repository Oversight Committee, Transgenic Models of Disease, Exploring the Role of Cancer Centers for Integrating Aging and Cancer Research, and Re-envisioning the Alzheimer's Centers Program: Results of a Planning Meeting.

Dr. Nadon described the conclusions of the Biospecimen Repository Oversight Committee that prior experience with biospecimen repositories has been that costs are higher than forecast, and usage is uncertain. Therefore the committee urged the gradual approach of starting with a web-site that would allow posting of resource availability and then developing a virtual repository if that site proved useful. Council members urged NIA staff to consider commercial sites for repository development (Staff is doing that.) They also questioned whether the intent is to develop a site that allows prospective study. Dr. Nadon indicated that the initial goal is to develop a retrospective tool.

Dr. Wise reported on the recent meeting on developing transgenic models in non-human primates and other animals. The rationale for the workshop was that current mouse models are of limited utility in studying certain human diseases. Workshop participants accepted that nonhuman transgenic models are possible and would bridge a gap in research models on dementing and other diseases. However, severe methodological and logistical problems remain in developing these models – not least is the extended lifespan of primates and other larger animals, making transgenic models of childhood disease more practical targets. The committee also considered non-transgenic approaches with primates.

Dr. Yancik reported on the advisory workshop that explored ways to integrate aging and cancer research through the use of the NCI Cancer centers. Recommendations were organized into areas of patterns of care; treatment efficacy and tolerance; effects of comorbidities on cancer; prevention risk assessment and screening; psychological, social and medical issues; palliative care, end-of-life care and pain relief; and the biology of aging and cancer. She indicated that the workshop has stimulated a joint initiative with NCI that is focused on using the resources of the NCI Cancer centers to enhance research on cancer and aging. The report produced from the workshop is available in print and on the web at: http://www.nia.nih.gov/ResearchInformation/nianci.htm .

Drs. Miller and Phelps described the recommendations of the workshop on the genetics of late-onset Alzheimer's Disease (LOAD) and Institute actions in response to the recommendations. Workshop participants strongly advocated that a sizeable national sample of families with a history of LOAD be available with appropriate controls. The existing NIA-supported Indiana cell bank appears appropriate as a starting point for this resource. Given its current status as a part of an existing center, staff recommended that it be separated from the center and become an independent cooperative agreement. Workshop recommendations also stressed attention to informed consent issues, the kinds and numbers of samples needed to establish an appropriate research resource in this area, and the continuing need for a precise standard for LOAD diagnosis.

Dr. Phelps described the advice obtained from a planning meeting considering the future of the Alzheimer's Centers program. The major points made by this group were that the Centers should be restructured to allow local variation in cores to match local strengths; that the Centers should consider non-clinic based samples; that a minimum data set should be developed and made widely available and that the NIA should continue to encourage more sharing and collaboration among the existing Centers. In response to a Council question about whether Alzheimer's Centers would have priority status in access to resources developed by the Centers, staff indicated that a minimum data set will be developed and made available to independent investigators. Another Council member raised the issue of privacy and confidentiality of data that may be available in a minimum data set.

With the above comments noted Council members approved the recommendations and resulting staff actions from the meetings and workshops.

A proposed advisory workshop was presented for concept clearance and discussion. Dr. Buckholtz described the Alzheimer's Disease Neuroimaging Initiative. The initiative will be modeled after the osteoarthritis initiative and will encompass interactions among academic investigators, the pharmaceutical industry, imaging manufacturers, NIH, the Alzheimer's Association, and Institute for the Study of Aging. The rationale for the initiative is to utilize ongoing clinical trials or set up new trials or longitudinal studies to look at both the natural history of neuroimaging in terms of brain changes over time, and also the possibility of using neuroimaging to serve as a surrogate marker in clinical trials. The goal of the advisory committee meeting is to determine future directions.

The Working Group on Program recommended to Council that the concept for the workshop planned and for initiatives that stem from it be approved. Council voted accordingly.

  1. Program Highlights

    A. Dr. Reubin Andres, of the NIA Intramural Program, presented a talk on “The Diabetes Prevention Program: Remarkable Age Differences in Effective Interventions.”

    The Diabetes Prevention Program (DPP) is a multi-center NIA/NIDDK-supported effort to prevent or to delay the development of diabetes in men and women who have been identified as having characteristics that place them at high risk of developing diabetes. Nearly half of the participants are members of minority groups. Two interventions have been tested: intensive life-style intervention (primarily loss of weight and increase in physical activity) and administration of an anti-diabetic medication, metformin. A third arm of the study was a control group that received a placebo. Subjects were carefully selected: they had to have (1) impaired glucose tolerance (a “grey zone” lying between definitely normal and definitely diabetic), (2) a fasting plasma glucose concentration that placed them in an increased risk zone, and (3) be overweight or obese. There were over 1000 volunteers in each of the three arms.

    In the planning phase of the study, there was concern that inclusion of older individuals would not succeed and would dilute the chances of showing beneficial effects in younger and middle-aged adults. Some of these concerns were familiar arguments to those with experience in studying older persons. For example, it was feared that older persons (1) might not choose to volunteer; (2) if they did volunteer, they would not or could not make the prescribed dietary changes; (3) if they were successful in losing weight, there might well be harm associated with the loss rather than benefit; (4) the selected medication might have serious side-effects; (5) the presence of multiple diseases and conditions associated with aging might confound the test results; (6) mortality rates could be so high that few subjects might complete the study; (7) their site of residence might be unstable as they made the decision to move into the Sun Belt. However, the investigators argued that older individuals would prove to be a very cooperative subset of subjects. In addition, the relatively high rate of development of diabetes in older individuals not only made it important to study them, but also made it likely that the study would gain statistical power. The NIA set the goal that 20 percent of the enrollees be 65 or more years of age.

    The first reports from the DPP have just been published ( N Engl J Med 346: 393-403, 2002) and differences in young and older age groups are reported. Twenty percent of the enrollees were 60 years of age or older (648 men and women). Conversion from the impaired to diabetic state was markedly reduced by the intensive life-style intervention and this was especially true of the older subjects. The metformin arm of the study showed striking age differences. Although the drug was effective in younger and middle-aged adults, it had no significant benefit in the older group.

    Overall, the data emphasize the importance of identifying individuals at risk for diabetes so that interventions can be initiated before diabetes and its long-term complications occur. The term “pre-diabetes” has been resurrected to describe this grey zone. There is cumulating evidence that harmful consequences are associated with glucose levels in this intermediate zone. Results from the Baltimore Longitudinal Study of Aging (BLSA) show that individuals who enter the “pre-diabetes” zone may have years of warning time, and that intensive efforts should be made to prevent, delay or reverse this early warning state. Indeed the BLSA results show that although some individuals progress rapidly to diabetes, it takes 18 years for half of the pre-diabetics to convert to diabetes. Screening for the pre-diabetic is useful especially in view of the DPP demonstration that effective preventive measures are available.

    Questions and discussion by Council raised issues concerning the stability of glucose test results carried out over time, the still to be solved problem of maintaining weight loss in the long term, and the question of whether benefits could be obtained with lower weight loss and activity goals. Important questions remain about the mechanisms underlying the differential effects of the two interventions in the elderly. Analyses of the data from this study are continuing. Future studies can now be designed with the evidence that the development of diabetes can indeed be significantly influenced.

    B. Dr. Richard Schultz, head of the Resources Enhancing Alzheimer's Caregiver Health (REACH) Coordinating Center at the University of Pittsburgh, described research supported by the Behavioral and Social Research Program. He presented the rationale for studying caregivers and their health outcomes, as well as interventions to reduce negative health outcomes. More than 54 million persons provide care to a family member or friend; approximately 60 percent of the adult population expects to be or is already a family caregiver. Most caregivers experience caregiving as a chronic stress. Caregiving usually includes physical, financial, and psychological strain, extended over many years, along with marital, parental, and work obligations that compete with elder-care.

    Physiologic and health studies confirm the perception of high levels of chronic stress. Schultz and Beach ( JAMA 282[23]: 2215-2219,1999) demonstrated that caregivers who reported experiencing caregiving strain had an adjusted relative risk of mortality of 1.63. Strained caregivers demonstrate significantly higher levels of health risk behaviors and depressive symptomology than do non-caregivers or non-stressed caregivers while caregiving, but significantly lowered levels when the care-recipient dies, nearly matching the bereavement levels of these symptoms in non-caregivers and non-strained caregivers (Schultz R, et al. JAMA 285[24]: 3123-3129, 2001).

    REACH was first funded by NIA/NINR in 1995 with the goal of examining the effectiveness of social, behavioral, and technological interventions aimed at strengthening family caregivers' capabilities of successfully providing care to demented persons. A secondary goal was to develop standardized outcome measures and methodologies to assess the effectiveness of specific interventions on caregivers and care-recipients. Six sites (Birmingham, Boston, Memphis, Miami, Palo Alto, and Philadelphia) and one coordinating center (Pittsburgh) were selected that offered a large sample size of multi-ethnic AD caregivers across multiple sites with randomized but unique interventions. A total of 1,222 caregiver/care-recipient dyads were recruited. Interventions included skill training, information and referral, environmental skills building, behavioral management training, stress management training and support, psychoeducational/coping training, and technological support. Control caregiver groups were provided with either usual care (informational literature only) or minimal support (i.e., empathic listening).

    Caregivers were assessed at baseline and every six months for 18 months for indications of caregiver stress and their ability to manage emergent caregiving problems. Meta analyses demonstrated differential efficacy of interventions, but no single intervention resulted in significant effects across all subject groups. When results were pooled across all sites, meta analyses revealed that active therapy was superior to the two control conditions. Other results include the identification of outcome measures with strong psychometric properties that are appropriate for culturally diverse populations and the identification of key intervention components likely to produce significant results.

    The second phase of this randomized clinical multi-site, multicultural intervention research (REACH II) is ongoing. Work is being completed to develop a uniform intervention that takes into account multiple challenges of caregiving. Attention has been paid to developing a standardized protocol that can be reproduced, yet dose-adjusted based on caregiver risk profile. Six hundred dyads will be recruited. Outcomes measures include depressive symptomology, levels of social support received, caregiver health risk behaviors, caregiver-reported burden, quality of care provided by caregiver, and caregiver risks appraisal.

    Council members inquired about the benefits of interventions based on caregiver age and gender. Dr. Schultz replied that there is variation in effectiveness as a function of the relationship of the caregiver to the care-recipient and the age of the person providing the care. One finding showed that women benefited more from the interventions than men did. However, some site-specific effects showed a greater benefit for men. This variability should be recognized as important in implementing interventions on a large scale.

    Council members inquired about secondary benefits for the care-recipient. Although REACH was not designed to produce or measure these types of effects across sites, Dr. Shultz reported that in multi-site intervention analyses, no single care-recipient benefit was identified. However, some site-specific interventions did show care-recipient benefits, for example, at one site the intervention delayed decline in functional status among the persons in the active treatment condition.

    C. Dr. Joseph Dillon, from the University of Iowa Medical School, described research supported by the Biology of Aging Program. In introducing Dr. Dillon, Dr. Frank Bellino made three points. First, there is a widespread public perception generated through the media and internet that dehydroepiandrosterone (DHEA), freely available in health food stores in this country as a dietary supplement, restores functions lost in aging when DHEA serum levels naturally decline. Second, DHEA administration to rodents, where it had been most studied and where the biology of DHEA is different from primates, protects rodents from obesity, diabetes and cancer. Human studies, while limited in numbers of subjects and time of exposure, are unimpressive and frequently not reproducible. Finally, while many have searched for a biologic receptor for DHEA to explain its activities, none has been found. The work Dr. Dillon described presented a convincing argument for a G protein-coupled receptor responsible for at least rapid effects of DHEA, and perhaps long-term genomic effects.

Dr. Dillon reported on newly published studies (Liu and Dillon, J Biol Chem , in press, 2002) in which his laboratory identified and biochemically characterized a putative G-protein coupled plasma membrane receptor for DHEA. Following epidemiologic studies implicating an anti-atherosclerotic effect of DHEA, he showed that physiologic concentrations of DHEA rapidly (within 5 min) affected nitric oxide (NO) production and endothelial nitric oxide synthase (eNOS) in bovine aortic endothelial cells (AEC). Based on the rapid, apparently non-genomic response, and his observations that DHEA coupled to bovine serum albumin produced the same NO response, he searched for a plasma membrane receptor in AEC. DHEA binding to this plasma membrane receptor from bovine and human AEC was high affinity, saturable, and specific. Exposure to pertussis toxin, which inactivates G proteins, blocked the DHEA effect, thus implicating G protein involvement. He subsequently identified Gai2 and Gai3 as the specific G proteins involved. Interestingly, estradiol did not interact with this receptor, although estradiol has similar interactions with another related receptor (Wyckoff et al., J Biol Chem 276: 27071-27076, 2001). This research is likely to lead to more specific studies of the biologic role of DHEA, independent of its role as a precursor for androgens and estrogens, and could better inform ongoing and planned human studies of DHEA therapy.

In response to questions about the receptor locus, Dr. Dillon responded that the receptor has been found in heart and fat tissue, with lower amounts in liver and none in kidney. More research is required to determine if potentially beneficial effects of DHEA can be separated from adverse effects by screening novel conformations of synthetic steroids. A separate nuclear receptor has not been ruled out, although others have searched so far unsuccessfully for such a receptor. Dr. Dillon emphasized that his laboratory has focused on the rapid action of DHEA. The DNA sequence for this receptor is being identified and characterized.

D. Dr. Scott Small, from Columbia University in New York City, gave a presentation on the use of functional magnetic resonance imaging (fMRI) to image subregions of brain temporal cortex to distinguish the development of Alzheimer's disease (AD) from non-AD memory decline.

The majority of healthy individuals above the age of 50 experience some form of memory decline. As individuals age in an environment rich with information and reliant on rapidly changing technologies, mild forgetfulness can be more than a nuisance. Moreover, there is the concern that mild forgetfulness is the harbinger of dementing illnesses such as AD. What the causes of age-related memory decline are, which can be treated or prevented, and how early AD can be distinguished from other more benign forms of memory decline are important clinical questions that remain unanswered and which serve as the main drive behind the research efforts of Dr. Small and his colleagues.

The hippocampal formation is a structure in the brain that plays an important role in normal memory. The hippocampus is a complex structure made up of separate subregions. These subregions are interconnected. The hippocampus functions like a circuit, so that lesions to any subregion will equivalently interrupt the circuit and cause overlapping memory deficits. A technique that could isolate which hippocampal subregion is most dysfunctional would aid in diagnosing the specific cause of memory decline. For example, if an individual with mild memory decline was found to have dysfunction in the entorhinal cortex, one of the five hippocampal subregions, we would suspect early AD; in contrast, if an individual had dysfunction in another subregion, e.g., the dentate gyrus, we would consider other age-related changes instead.

Currently available techniques assess the function of the hippocampus as a whole. They can determine that the global circuit is malfunctioning, but these techniques cannot pinpoint the specific hippocampal subregion that is the source of the circuit breakdown. fMRI is a relatively new imaging technique that can, in principle, detect subtle causes of brain dysfunction. In the last few years, Dr. Small's group has been testing different modifications of fMRI designed to increase spatial resolution so that fMRI can be used to assess the function of individual hippocampal subregions.

Metabolism is the rate in which the brain consumes oxygen to supply its energy needs. Most fMRI studies examine acute changes in hippocampal metabolism caused by having a subject perform a task. Since these metabolic changes are fleeting, images of the brain must be acquired rapidly, and, because of this each image has limited spatial resolution. Most causes of memory decline alter the chronic metabolic state of the hippocampus, not just its ability to change acutely. Therefore, if hippocampal images could be acquired more slowly, this would increase spatial resolution. In a series of recently published studies, Dr. Small and colleagues found that they could generate high-resolution maps of the hippocampal formation that allowed them to isolate the individual hippocampal subregions. By studying humans with mild forgetfulness and with Alzheimer's disease, as well as mice with memory deficits very similar to those of humans, they found that they could use this tool to dissociate individuals with memory decline based on the patterns of dysfunction measured from the subregions (Small SA, et al. Neuron 28: 653-664, 2000. Small SA, et al. Ann Neurol 51: 290-295, 2002).

In response to Council questions about the utility of fMRI for differential diagnosis, Dr. Small replied that they are currently performing follow-up studies to validate that high-resolution metabolic maps of the hippocampus can diagnose the early stages of AD and distinguish early AD from non-AD types of memory decline.

  1. Adjournment

The 86th meeting of the National Advisory Council on Aging was adjourned at 1:30 p.m. on May 22, 2002. The next meeting is scheduled for September 24-25, 2002.

Attachments:

  1. Roster of Council Members
  2. Director's Status Report to the NACA
  1. Certification

I hereby certify that, to the best of my knowledge, the foregoing minutes and attachments are accurate and complete. [3]

______________________________________
Richard J. Hodes, M.D.
Chairman, National Advisory Council on Aging
Director, National Institute on Aging

Prepared by Miriam F. Kelty, Ph.D.

Attachment A

MEMBERSHIP ROSTER
NATIONAL ADVISORY COUNCIL ON AGING
NATIONAL INSTITUTE ON AGING
(All terms end December 31 with the exception of those names marked with an * which were extended until June 30, 2002)

Chairperson
Richard J. Hodes, M.D.
Director
National Institute on Aging
National Institutes of Health
Bethesda, Maryland 20892


Ausiello, Dennis A., M.D. (2003)
Chief, Medical Services
Massachusetts General Hospital
Boston, Massachusetts

Cambier, John C., Ph.D. (2003)
Ida and Cecil Green Professor and
Chairman, Integrated Dept. of Immunology
University of Colorado Health Sciences Center
and National Jewish Medical & Research Center
Denver, Colorado

Campisi, Judith, Ph.D. (2002)
Senior Scientist
Division of Cell and Molecular biology
Lawrence Berkeley Laboratory
University of California
Berkeley, California

Dobrof, Rose W., DSW (2002)
Brookdale Professor of Gerontology
Brookdale Center on Aging
Hunter College of the City of New York
New York, New York

Espino, David V., M.D. (2004)
Professor
Department of Family & Community Medicine
Division of Community Geriatrics
University of Texas Health Science Center
San Antonio, Texas

*Gage, Fred H., Ph.D. (2001)
Professor
Laboratory of Genetics
The Salk Institute
La Jolla, California

*Harper, Mary S., Ph.D. (2001)
Geropsychiatric Research Consultant
and Distinguished Adjunct Professor
The University of Alabama
Tuscaloosa, Alabama

Kuller, Lewis H., M.D., DrPH, MPH (2004)
Professor and Chairman
Department of Epidemiology
Graduate School of Public Health
University of Pittsburgh
Pittsburgh, Pennsylvania

Prusiner, Stanley B., M.D. (2004)
Director and Professor
Institute for Neurodegenerative Diseases
School of Medicine
University of California
San Francisco, California

Riggs, Judith A., M.A. (2004)
Washington, D.C.

*Selkoe, Dennis J., M.D. (2001)
Professor of Neurology and Neuroscience
Center for Neurologic Diseases
Brigham and Women's Hospital
Boston, Massachusetts

Siegler, Ilene C., Ph.D., MPH (2003)
Professor of Medical Psychology
Dept of Psychiatry & Behavioral Sciences
Duke University
Durham, North Carolina

*Vaupel, James W., Ph.D. (2001)
Director and Professor
Max Planck Institute for Demographic Research
Rostock, Germany

*Wei, Jeanne Y., M.D., Ph.D. (2001)
Senior Physician
Division of Gerontology
Beth Israel Deaconess Medical Center
Boston, Massachusetts

Weisfeldt, Myron L., M.D. (2002)
William Osler Professor of Medicine
Director, Department of Medicine
Johns Hopkins University School of Medicine
Baltimore, Maryland

Wise, David A., Ph.D. (2002)
Professor
National Bureau of Economic Research
Cambridge, Massachusetts

Wise, Phyllis M., Ph.D. (2003)
Dean, Division of Biological Sciences
University of California Davis
Davis, California

Ex Officio Members

Tommy G. Thompson
Secretary
Department of Health and Human Services
Washington, D.C.

Ruth L. Kirschstein, M.D.
Acting Director
National Institutes of Health
Public Health Service
Bethesda, Maryland

Colonel George F. Fuller, M.D.
USUHS
Department of Family Medicine
Bethesda, MD

James F. Burris, M.D., F.A.C.P. F.A.C.C.
Deputy Chief Research and Development Officer
Office of Research and Development
Department of Veterans Affairs
Washington, D.C.

John Wren
Director, Office of Program Development
Administration on Aging, DHHS
Washington, D.C.


[ 1 ] For the record, it is noted that members absented themselves from the meeting when the Council discussed applications (a) from their respective institutions, or (b) in which a conflict of interest may have occurred. This procedure only applied to applications that were discussed individually, not to "en bloc" actions.

[ 2 ] For the record, it is noted that members absented themselves from the meeting when the Council discussed applications (a) from their respective institutions, or (b) in which a conflict of interest may have occurred. This procedure only applied to applications that were discussed individually, not to "en bloc" actions.

[ 3 ] These minutes will be approved formally by the Council at the next meeting on September 24-25, 2002, and corrections or notations will be stated in the minutes of that meeting.


Page last updated Feb 16, 2008