Council Minutes - May 2003

National Advisory Council on Aging

Summary Minutes: The Eighty-Ninth Meeting

May 20-21, 2003

CONTENTS

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

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

The 89th meeting of the National Advisory Council on Aging (NACA) was convened on Tuesday, May 20, 2003, at 3:00 p.m., in Building 31, Conference Room 10, 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 20, from 3 p.m. 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 21, from 8:00 a.m. to 1:45 p.m.

Council Participants:

Dr. Dennis Ausiello
Dr. Marie Bernard
Dr. John C. Cambier
Dr. David Espino
Dr. F. Michael Gloth
Dr. Eugene M. Johnson, Jr.
Dr. Lewis H. Kuller
Dr. Ronald Lee
Dr. Stanley Prusiner
Ms. Judith Riggs
Dr. Ilene C. Siegler
Dr. Leon J. Thal
Dr. David A. Wise
Dr. Phyllis Wise

Ex-officio Participants:

Col. George F. Fuller, M.D. (USUHS, DOD)

Absent:

Dr. James Burris (VA)
Dr. Judith Campisi
Dr. Rose Dobrof
Mr. Peter W. Nauert
Dr. Myron L. Weisfeldt
Mr. John Wren (AoA)

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

Members of the Public Present:

Mr. Kevin Beverly, Social and Scientific Systems, Inc.
Ms. Joan Goldberg, American Society for Bone and Mineral Research (ASBMR)
Ms. Mariana Gonzalez del Riego, Constella Group, Inc.
Ms. Jennifer Hedrick, Population Association of America (PAA) and Association of Population Centers (APC)
Dr. Ken Langa, University of Michigan
Dr. Rose Maria Li, Constella Group, Inc.
Ms. Stephanie Reed, American Association for Geriatric Psychiatry (AAGP)
Ms. Carol Schutz, Gerontological Society of America (GSA)
Mr. Roy Sewall, Social and Scientific Systems, Inc.
Ms. Ase Sewall, Social and Scientific Systems, Inc.
Dr. Sally P. Stabler, University of Colorado School of Medicine
Ms. Sara Thompson, National Mental Health Association

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

Ms. Lora Kutkat, OSP, OD, NIH
Cheryl Wiggs, CSR, NIH

Review of Applications

This portion of the meeting was closed to the public, in accordance with the determination that it concerned 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 731 applications requesting $673,007,208 for all years underwent initial review. Council recommended 463 for a total of $457,284,050 for all years. The actual funding of the awards recommended is determined by the availability of funds, percentile ranks, priority scores, and program relevance.

Call to Order

Dr. Hodes called the meeting to order at 8:25 a.m. on Wednesday, May 21, 2003, and welcomed members.

Director's Status Report

Dr. Hodes began the meeting with a discussion of the scientific Roadmap for the NIH, an initiative launched by the NIH Director to identify the major scientific challenges, opportunities, and roadblocks to progress. Particular interest has centered upon issues that cannot be accomplished easily by a single Institute, but can be considered the responsibility of NIH as a whole. As part of this process, which began in August 2002, the NIH Director convened meetings with a series of outstanding scientists and thinkers from across the country to identify priority areas of research. This information was collated and discussed at the September annual Leadership Forum of NIH Institute directors, and was translated into concept papers in November 2002. Since then, approximately 17 Roadmap workgroups have been formed, two of which were co-chaired by Dr. Hodes, with participation by several NIA staff members. These activities will feed into the NIH budget retreat in June 2003, and also will be incorporated into remarks by the NIH Director in July 2003 to the HHS Secretary's Budget Council.

Three very broad themes emerged from the NIH Roadmap activities:

• New Pathways to Discovery – to identify the high through-put, large scope initiatives that would facilitate broad areas of research, such as genomics, proteomics, nanotechnology, bioinformatics and computational biology, molecular imaging, and molecular libraries. A working group on “Building blocks” of biological research is co-chaired by Dr. Francis Collins (NHGRI) and Dr. Hodes.
  
• Research Teams of the Future – to look more broadly at supporting multidisciplinary teams and high-risk/high-return research, as well as ways to optimize interactions among for-profit foundations, and other communities. Dr. Hodes is co-chairing a workgroup on private-public partnerships with Dr. von Eschenbach, Director, NCI.
  
• Re-engineering the Clinical Research Enterprise – to facilitate greater integration of clinical research networks and informatics, better training and career development, and more effective communication between basic/applied researchers and the public.

The time frame projected to achieve long-term goals may be 8-10 years with associated risks or challenges that can be assessed through thoughtful planning.

Dr. Hodes turned next to the NIA budget. He recalled that NIA had crossed the billion-dollar level in funding. However, in FY2003 a recision across all of government pushed the NIA budget down to $993,598,000, still a healthy 11.6 percent increase from the FY2002 total. NIA has been consistent in investing close to two-thirds of its budget in research program grants (RPGs). Thus, doubling the NIA budget during the last five years has translated into the same doubling of funds into RPGs. The number of grants has not doubled, because average cost of grants has been increasing. Over the past 5 years, costs of awards have increased by approximately 40 percent and the number of awards has increased by 40 percent across NIH.

In terms of other budget categories, Dr. Hodes noted that the NIA intramural program accounts for approximately 9.7 percent of the budget, and administrative costs (including staff costs) account for approximately 3.3 percent. The Centers program, at approximately 8.4 percent of the NIA budget, has grown less rapidly than the overall budget.

Dr. Hodes also showed the trend in appropriations and RPG success rates since FY1994. In the period 1995 through 1998, NIA funding increases were in the 3 to 7 percent range. The current President's 2004 budget shows a very modest increase over 2003. As the flattening will occur after a period of doubling, the resources for next year will remain substantial.

During the period FY1994 - FY2003, grant success rates at NIA fluctuated between 26 and 34 percent, with an estimated 31.3 percent in FY2003. With a flat budget, Dr. Hodes conjectured that the grant success rate would decrease into the mid-20s, but he cautioned that this estimate is very crude, as the final budget as well as future numbers of grant submissions are uncertain.

Dr. Hodes then discussed percentage increases in funding mechanisms between FY2002 and FY2003. The total NIA budget increased approximately 12 percent, and total RPGs and Small Business Innovative Research (SBIRs) increased by approximately the same percent. The other grant mechanisms (Centers, Other Research, Training, R&D Contracts, Intramural Research, and Research Management Support [RMS]) all increased less than 12 percent. The increase in funding for centers was marginally above inflation, and higher stipends drove the increase in training funds. R&D contracts increased approximately 27 percent; two-thirds of this increase is attributable to taps at the Department level, which are used to fund other federal agencies and programs. The actual R&D contract funds available for NIA-funded research increased at a lower rate than did RPG funding.

As part of the President's administrative policies, all of the Federal Government has been looking at possible ways for increasing efficiency, and for decreasing the size of government, when appropriate. What is striking is that, while the budget has increased dramatically over the past 10 years, the number of employees (Full Time Equivalents [FTEs]) at NIH has not increased. Dr. Hodes recognized the challenges in maintaining the proper stewardship of grants, given increased responsibilities and workload.

Following Dr. Hodes' report, Council members raised a number of issues for discussion. One Council member commented that, over the past decade, there have been several successful intervention outcomes and clinical trials in the aging arena, demonstrating the efficacy of therapies. The Council member asked Dr. Hodes to clarify the role of NIA in relation to that of the Centers for Disease Control and Prevention (CDC) and other Department of Health and Human Services (DHHS) units, regarding the translation of research findings to applications. Dr. Hodes responded that translating outcomes from NIA research (e.g., the recent diabetes prevention trial or the exercise interventions that NIA has been supporting) into changes in public behavior poses a formidable challenge. NIA is committed to working in partnership with the CDC and the rest of DHHS to communicate the results of NIA-supported research.

Another Council member questioned the presumption that the lack of growth in NIH staff despite doubling of the NIH budget is necessarily an issue, since technological advances could justify a reduction in staff, particularly non-scientific staff. Dr. Hodes agreed that increases in efficiency or automation may offset the need for added staff, and an increasing emphasis upon electronic communications (including for receipt and review of applications) has helped. However, he noted that other factors point to the need for increased staff, including, for example, implementing new regulations or responsibilities regarding communication with the public. NIH continually seeks to identify areas where reorganization or greater economies are possible, and highlight other areas where an increase in staff is needed to fulfill the NIH mission.

One Council member suggested that lengthening the grant period of performance for productive grantees could help reduce the administrative burden. Dr. Hodes reflected that this issue has been discussed most extensively in relation to clinical trials, in which it is argued that results often cannot be obtained in five years. A balance must be maintained between avoiding undue burden and providing responsible peer review and opportunities for competition. A longer than five-year award now requires a single case deviation from policy on length of award. NIA has been flexible in considering special cases in the interests of science.

Another Council member wanted to know whether NIA has a special niche to fill, distinct from other institutes or HHS agencies, regarding two issues that he considered to be critical to aging research: (1) the impact of overpopulation and the associated increased risk for disease upon the elderly; and (2) the greater vulnerability of older people to bioterrorism attacks, compared to the average population. With regard to the second point, Dr. Hodes stated that NIA's activities in the area of elderly susceptibility or vulnerability to bioterrorism have been modest in comparison to those of NIAID. However, NIA continues to support related research, for example in the area of immune response to bioterrorism agents or infectious diseases (e.g., smallpox). The older population has been immunized to smallpox, so intramural and some extramural research has focused upon examining the residual immunity against smallpox. NIA also supports research into vaccine development and immune response, particularly among older hosts in both animal and human systems. Another aspect has been the psychological and emotional/behavioral side of biodefense or bioterrorism. NIA has been interacting with NIMH on these topics, for which NIMH has taken the lead. Dr. Hodes welcomed suggestions by Council members on topics that might be given greater attention.

With regard to the first point, Dr. Hodes described increased interactions between NIA and the National Institute of Environmental Health Sciences (NIEHS) to support research examining the impact of the environment, over time, on people as they age. Another Council member remarked on the apparent lack of coordination between the NIA and the Environmental Protection Agency (EPA). Dr. Hodes agreed that NIA could engage in more intensive and ongoing communication with other arms of the government.

Discussion turned next to the availability of funding mechanisms to support research that can be conducted on a quick turnaround timeframe to respond to an urgent problem, such as bioterrorism or natural catastrophes (e.g., Severe Acute Respiratory Syndrome [SARS]).
Dr. Hodes stated that NIA and NIH have rapid deployment capabilities in place, and could support clinical trials of immunization in specific or targeted populations. He also concurred that older subjects must be drawn from normally inaccessible settings, such as long-term care facilities and other institutional settings. Although the private sector has supported some trials (for example, in influenza), Dr. Hodes noted that not all drug or vaccine development will be sufficiently profitable to drive commercial research, particularly with liability risks. It may be necessary for the Federal Government to have a role in guaranteeing, underwriting, or in some other manner collaborating with the private sector, to increase incentives. A change in principle and outlook, at least over the last five years, has been to realize that federally-supported research must take a more active role in ensuring that necessary research is performed and vaccines are developed.

Building further upon the discussion about translating research findings into practical information, one Council member asked whether NIA would consider developing a Web-based system to share information regarding the most current geriatrics practice guidelines (e.g., on diabetes treatment or prescription of statins) to make guidelines available to clinicians or members of the public. Dr. Hodes noted that establishing practice guidelines is not within the purview of the NIH, but that NIH-supported research clearly is an important factor in informing such guidelines, and the NIH can (and does) convene consensus conferences on specific issues. Another Council member noted that the government runs a guidelines clearinghouse, which anyone can access and search. The NIA does provide general guidance, offers information about institutions and websites, and produces Age Pages (available in hard copy and on the NIA website), providing general guidance on particular conditions.

Some Council members expressed concern that, although NIH has been successful in supporting basic research, it has been difficult to disseminate the information quickly to the medical community and the public. Physicians instead are obtaining most of their information from drug companies. Examples of findings that do not appear to have reached the mainstream include:

• The greater relevance of biological aging over chronological age;
  
• Results of lipid-lowering trials that have focused specifically upon the elderly and have shown benefits in reducing atherosclerosis and cardiovascular disease;
  
• Findings indicating that measurements of serum cholesterol in the elderly predict little, as many older people may have serious atherosclerosis;
  
• The recently recognized need for the elderly to take two or three drugs in order to lower blood pressure and keep it down.

Dr. Hodes described one concerted effort by NIA to spearhead an information campaign that publicized the benefits of immunizing older men and women against influenza. The campaign targeted primary care physicians, as well as the elderly themselves. This campaign was so successful that the vaccine was out of stock by the following flu season. Another example involved behavioral interventions, such as exercise and physical activity. NIA research indicates that elderly people who embarked upon a modest program of a healthy diet and physical activity experienced more than a 70 percent decrease in diabetes. In light of these findings, NIA has disseminated more than half a million copies of an exercise guide. Dr. Hodes described the ways in which NIA staff members currently are examining outcome measures, to understand the impact that information dissemination efforts have had on behavior. One Council member suggested that NIA consider a public-private partnership to enhance the dissemination of research results.

One Council member returned to the issue of the likely modest increases in the NIA budget over the next few years, and wondered what might result in larger increases. Dr. Hodes expressed gratitude for the support of various constituents to bring about the doubling of the NIH budget. He recognized the inherent complexities in trying to sort out differential needs or priorities. NIH has benefited from focusing on raising the support for NIH as a whole; it also has benefited from discouraging the practice of earmarking funds for particular diseases. This strategy has worked well when the budget was doubling. However, during a period of reduced or absent budget growth in the coming years, there will be a particular need to address differential growth. Activities such as the NIH Roadmap are a way to systematically identify and capitalize upon research opportunities.

The NIA's work has been seen as particularly relevant and opportune, because of concerns about the future of the Medicare and Medicaid budgets, as well as growing recognition of the high cost of chronic diseases, particularly when they co-occur. At the same time, there is a need for accountability for funds invested in the NIH and for their efficient use.

Future Meeting Dates

• September 23-24, 2003 (Tuesday-Wednesday)
• February 3-4, 2004 (Tuesday-Wednesday)
• May 24-25, 2004 (Monday-Tuesday)
• September 22-23, 2004 (Wednesday-Thursday)

Consideration of Minutes of Last Meeting

The minutes of the February 2003 meeting were considered. A motion was made, seconded, and passed to approve the minutes.

3. Report: Task Force on Minority Aging Research

Dr. David Espino began his report on behalf of the Task Force on Minority Aging Research by sharing a success story: He praised the staff for an outstanding job in providing administrative minority supplement support and mentoring. He then observed that the number of administrative supplement requests has been increasing without increasing support. In light of this, the Task Force discussed ways to maintain enthusiasm in the field; however, no consensus was reached. The second issue that Dr. Espino raised was the under-representation of minority investigators, in terms of the numbers of applications for career development awards. The Task Force agreed to consider an initiative targeted particularly towards the needs of this group.

4. Reports: Working Group on Program and Clinical Investigators Working Group

1. Advisory Meetings, Conferences, and Workshops

Dr. Phyllis Wise, Chair of the Working Group on Program, asked those who had reported at the previous day's meeting to review the actions and recommendations related to NIA-sponsored advisory meetings. A motion was made, seconded, and passed to accept the reports, recommended actions on the meetings, and the RFA concepts.


Proteomics and Aging

Dr. Felipe Sierra reported that a workshop was held on December 10-11, 2002, to discuss NIA's efforts in the area of proteomics and aging. The workshop convened more than 20 leading investigators in the relevant fields, and generated recommendations for next steps. Dr. Sierra reported that a main point of discussion at the meeting centered upon the need for standard parameters to facilitate analysis and replication. One of the goals is to develop a Request for Applications (RFA) specifically applied to the field of aging.


Dietary Supplements and the Elderly

Dr. Judy Finkelstein reported on a workshop held January 14-15, 2003. The workshop was sponsored by NIA, the Office of Dietary Supplements (ODA), and several other NIH Institutes. It examined usage of dietary supplements, the implications for the elderly population, and evidence-based studies. The recommendations for future work include database analysis, methodology, behavioral studies, and clinical and basic science studies. Dr. Finkelstein is working with other ICs to develop a program announcement in this area.


Research Needs in the Evaluation of Executive Functions from Cognitive Aging to Dementias

Dr. Elisabeth Koss reported on a workshop held January 27-28, 2003, which focused on the need to develop further the concept of executive functions. Experts from three scientific approaches, animal models, imaging, and clinical research, were invited to discuss common threads, instrumentation, and mechanisms of evaluation. The group recommended (1) that a better test be developed to evaluate executive functions, (2) that the term “executive functions” needs further definition, and (3) that we should start studying these functions in middle age. Other recommendations included the need for epidemiological and imaging studies, as well as the need for a follow-on workshop. Currently, a workshop is planned for June 2003, to be conducted in collaboration with other ICs, that will focus on a trans-NIH initiative.


Mechanistic Basis of Hutchinson-Gilford Syndrome (follow-up)

Dr. Huber Warner reported that NIA is planning a second workshop, July 28-29, 2003, cosponsored by the National Human Genome Research Institute (NHGRI) and the Progeria Research Foundation. This workshop will follow up on the discovery of the lamin mutation, both to better understand Hutchinson-Gilford syndrome and its mechanistic basis, and to discuss whether and how this syndrome may inform our understanding of normal aging. He reminded the Council that Dr. Maria Erickson presented at the last Council on Hutchinson-Gilford Progeria Syndrome. She also was first author on a recently published paper regarding the identification of this gene (Erickson, et al. Nature 423[6937]: 293-8, 2003).


Clinical Investigator Career Development Award

Dr. Judy Salerno reported that the NIA Clinical Investigators Working Group has made great progress in negotiations with the foundations regarding a joint public-private partnership for a Beeson-type career development program. The program's purpose primarily is to encourage the development of future leaders in the field of aging by helping faculty members early in their careers to gain additional research training and establish independent programs in aging research. The Working Group seeks to build a career development path that selects those with considerable promise for careers in aging research for a 5- to 7-year award. This award will be flexible with respect to time and amount, with a total amount between $500,000 and $700,000 during the 5- to 7-year period. The group is working on a draft RFA and plans for late 2004 awards. Council members thanked Dr. Salerno for her leadership on this issue, and were pleased with the progress.


Health and Retirement

Dr. Laura Shrestha reported on a planned RFA by the Behavioral and Social Research (BSR) program, focusing on the development of an integrated approach to the determinants of work and retirement decision-making, as well as the economic and health-related consequences of these choices in later life. The RFA is intended to encourage the analysis of existing data sets supported by the NIA, such as the Health and Retirement Study (HRS), the Panel Study of Income Dynamics (PSID), and the English Longitudinal Study of Aging (ELSA).


2. Report of Neuroscience and Neuropsychology of Aging Program Review

Dr. Phyllis Wise reported that the Neuroscience and Neuropsychology of Aging (NNA) Program Review took place on May 19, 2003. The review group was comprised of six Council members and two outside experts. Reviewers complimented the staff for their excellence, their ability to remain in contact with their growing roster of grantees, and their commitment to encouraging young investigators to submit first grant applications. Reviewers praised the scope of the portfolio for being balanced, excellent, and broad-reaching, and supported the addition of an R21 mechanism to support exploratory studies. The review group encouraged the use of program announcements (PA) over Requests for Applications (RFA), because there was a sense that PAs might yield higher quality applications. The group commented that a reevaluation may be needed regarding whether or not all of the Alzheimer's Research Centers (now numbering 29, with 3 pending) need to be continued. The group also encouraged the program to continue to set priorities and strategies for funding, taking into consideration the fact that (1) clinical trials are extremely expensive, and (2) continued funding for imaging is seen as vital to future research. The only major concern centered upon the impact of increased workloads and other constraints on staff, and the impact of outsourcing. A number of Council members intend to communicate with the Secretary in support of the staff's ability to continue their fine work.

In discussion, it was noted that it is unclear whether the number of centers needs to be reduced. It was clear, however, that centers are being asked to shoulder more responsibility for administration, particularly in the areas of collaborative and multi-center projects. The centers are a highly visible portion of the NIA portfolio, and invaluable for bringing large groups of individuals to work on a single problem. As staff grapples with the future direction of the centers, they must balance the number of Centers with the Centers' ability to accomplish their task.

Dr. Andrew Monjan thanked the reviewers on behalf of Dr. Marcelle Morrison-Bogorad, Associate Director for the NNA Program.

3. Revised Statement of Understanding

The Working Group considered a proposed change to the Statement of Understanding: not to count facilities and administrative (F&A) costs from subcontracts against the $100,000 limit for direct costs. With this change, multi-institutional awards now will have the same functional threshold as single institution awards when the Council is considering administrative supplement requests. A motion was made, seconded, and approved to allow this revision to the Statement of Understanding.

5. HIPAA: How It Affects Research

Dr. Lora Kutkat, Office of Science Policy, NIH, presented an overview of the implications of the Privacy Rule from the Health Insurance Portability and Accountability Act (HIPAA) for NIH-supported research. How the Privacy Rule will affect research depends upon who the researcher is, whether he or she works for a “covered entity,” and whether “protected health information” (PHI) is being sought. States' laws also may complicate the picture, if their laws are more stringent than the Privacy Rule, which Ms. Kutkat described as working in concert with other existing laws and guidelines to provide further privacy protections. Ms. Kutkat highlighted several new concepts introduced by the Privacy Rule that were not addressed prior to the Privacy Rule compliance date of April 14, 2003. For example, an individual's signed authorization is generally required for uses and disclosures of his or her identifiable health information. This requirement can be waived by an Institutional Review Board (IRB) or a Privacy Board. Finally, accounting for disclosures also is generally required under the rule. Ms. Kutkat then discussed acceptable ways to access data and when authorization is required.

Ms. Kutkat stressed that NIH's role is not to enforce HIPAA, but rather to educate researchers. The NIH has worked with Food and Drug Administration (FDA) and CDC to publish guidance about what HIPAA entails for researchers. The information is accessible at http://privacyruleandresearch.nih.gov/resources.asp . Guidance is also available regarding sample authorization language, IRBs, Privacy Boards, clinical research, repositories, and databases.

Ms. Kutkat fielded a number of questions from the floor. A scenario was posed in which a grant is awarded to a non-covered entity (e.g., the School of Public Health at a university) but involves collaborators from a covered entity (e.g., the Medical School at the same university) who may not be working in the covered entity while working on the specific grant. Would the Principal Investigator (PI) be required to comply with the HIPAA Privacy Rule in this case? Ms. Kutkat stated that this decision would need to be made by the institution.

One Council member raised the issue that older scanners may not be able to de-identify subjects, because the scanner system requires PHI to operate. Ms. Kutkat noted that in two years, the HIPAA Security Rule becomes effective. At that point, information systems will need to be fully compliant.

A question was raised regarding the need for authorization by third parties from whom information is collected by a research subject. The Department has not completed review of the guidance for third parties, but Ms. Kutkat offered to relay back to the NIA Council the answer to this question.

6. Program Highlights

1. Neuroscience and Neuropsychology of Aging: The Relationship of MRI to Dementia in the Cardiovascular Health Study (CHS)

Dr. Lewis Kuller, University Professor of Public Health, Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, presented his findings from the Cardiovascular Health Cognition Study, a sub-study of the Cardiovascular Health Study (CHS), is probably the largest incident dementia study in the world. The investigators evaluated 3,608 participants who had a magnetic resonance imaging (MRI) of the brain in 1992-94; participants have been followed to 1998-99 on the incidence and risk factors for dementia and specific types of dementia. The diagnosis of dementia was based upon neurological exam, neuropsychological testing, interviews with proxies, and review of medical records. All diagnoses were validated by a panel of experts in dementia diagnosis, using standardized criteria. There were 480 incident dementia cases during the study, with an average of six years of follow-up; 227 cases were prevalent at the baseline, totaling 707 dementia cases in the study. In 1997-1999, a repeat MRI study was conducted. Before looking at the MRI, and based only upon standard classification of Alzheimer's disease vascular dementia by the expert review, approximately 70 percent of the incident cases were classified as Alzheimer's disease, with approximately 27 percent having some vascular component.

The reported incidence of dementia is slightly higher than in other U.S. studies, but is comparable to the incidence of dementia reported in Europe, especially from Rotterdam and some of the larger European studies. Dr. Kuller attributed the slightly lower incidence in American studies to the tendency to exclude deaths in the cohort. By age 75, dementia incidence rates are substantial, with incidence rates of approximately 3 to 4 percent per year, increasing according to age, as might be expected. Incidence rates for non-whites were approximately a third higher, possibly due to an ascertainment bias, because of the diligent efforts to make diagnoses in the African American population. There appeared to be no sex difference for either blacks or whites once age was standardized.

After adjusting for age and applying a Cox proportional hazard model, predictors of dementia include race, education, atrophy of the ventricles on the MRI, high white matter grade on the MRI, having one or more subcortical infarct, and Apo E-4 . Apo E-4 is strikingly related to Alzheimer's disease, while high white matter grade is more closely related to vascular dementia, as is the number of large infarcts on MRI.

Dr. Kuller stated that we can predict dementia better than we can predict coronary disease. If one factors in the combination of Apo E-4 , cognition, high white matter grade, and high ventricular grade, the odds ratio of developing dementia is increased 17-fold.

The participants with vascular dementia have more infarcts than do those without vascular dementia. The majority (approximately 70 percent) of first infarcts on MRI are subcortical in the basal ganglia, without presenting any symptoms. Although the link is clear between silent infarcts and the risk of clinical stroke, it remains to be shown that these infarcts contributed to the dementia.

If the vascular lesions are important, then we have effective preventive treatment possibilities.

Dr. Kuller believes experimental tests are needed to see if changing the known risk factors that lead to vascular disease in the brain reduce the risk of dementia. However, conducting a placebo-controlled trial is difficult when treatment for the condition under study is available. SysEuro, a study conducted in Europe with a calcium channel-blocker as the primary drug, reported a 40 percent reduction in dementia or Alzheimer's disease. The effect is substantial though a number of investigators question its replicability.

In response to questions from other Council members, Dr. Kuller stated that his team has undertaken some analysis of unilateral infarcts versus bilateral infarcts, and he remains doubtful that bilateral infarcts are necessary for vascular dementia. He believes that the vascular component makes dementia appear earlier or progress more rapidly. He acknowledged that current literature includes many arguments that vascular disease is a major contributor to Alzheimer's disease pathology (In eds. de la Torre JC, et al., Ann NY Acad Sci , Vol 977, 2002). Vascular disease probably has many different etiologies and is difficult to untangle. A complication arises, in that if one can decrease the risk of both stroke and coronary disease, the prevalence of dementia could very well increase due to the improved life expectancy caused by averting stroke or coronary disease.

2. Biology of Aging: Longevity Assurance Gene (LAG) Initiative and Control of Lifespan and Metabolism in C. elegans

Dr. Anna McCormick from the Biology of Aging Program presented findings from a paper by NIA grantee Dr. Gary Ruvkun (Harvard Medical School) and his colleagues that looked at the control of lifespan and metabolism in the nematode Caenorhabditis elegans (Lee et al., Science 300: 644-647, 2003). In particular, the daf-16 target genes were studied to decipher how the lifespan and metabolism of C. elegans are regulated. This topic was selected to highlight a study in the NIA Longevity Assurance Gene (LAG) initiative, and to portray the impact of technological advances, such as bioinformatics and RNA interference (RNAi), on the study of the basis of longevity, aging, and age-related diseases.

Previous studies in the worm C. elegans have shown that the daf-2 signaling pathway controls longevity, metabolism, and development, and that equivalent receptor signaling pathways regulate longevity and metabolism in the fly ( Drosophila melanogaster ) and in mice. (The daf-2 signaling pathway in worms has the same function as the insulin growth factor-1 [IGF-1] signaling cascade in mammals.) In the worm, the daf-2 signaling pathway may be regulated by approximately 37 ligands, some of which already have been identified. However, it is not yet known which ligands are involved in regulating longevity.

The daf-2 mutant worm (decreased daf-2 signaling), originally discovered by Dr. Cynthia Kenyon, has up to a three-fold increase in lifespan depending on whether there is a single mutation or multiple mutations on the pathway. About 5 years ago, both Dr. Ruvkun's and
Dr. Kenyon's laboratories found that the daf-16 gene is the major gene that regulates this daf-2 signaling cascade with respect to longevity. This gene encodes a forkhead transcription factor, which is negatively regulated by daf-2 signaling and translocates into the nucleus when daf-2 signaling is abrogated. Conversely, DAF-16 mediates the functions of the daf-2 pathway when a mutation to the daf-2 gene results in either a lack of function or a reduction of function. Protein products of the mammalian daf-16 orthologs, genes related to daf-16 by common phylogenetic descent, have been identified as FOXO1, FOXO3, and FOXO4.

It is now known that the daf-2 pathway and the DAF-16 transcription factor regulate longevity and metabolism in C. elegans , Drosophila , and mice. The DAF-16 transcription factor and its analogous counterpart in humans (i.e., homolog), the FOXO transcription factor, bind identical DNA consensus sequences. To test the hypothesis that DAF-16/FOXO controls homologous target genes in different species to mediate longevity and metabolism, Dr. Ruvkun utilized bioinformatics and a comparative genomics approach to search for DAF-16 binding sites in the C. elegans and Drosophila genomes, and to identify which of these genes were orthologous to one another. He was able to identify 17 orthologous genes with DAF-16 binding sites in the promoter region, several of which had homology in human, C. elegans , and Drosophila DNA.

Dr. Ruvkun found that 6 of the 17 candidate genes were differentially expressed in wild type (WT), daf-2, and daf-2/daf-16 mutants, indicating that their expression was regulated by daf-2 signaling through DAF-16. Three of these six genes were expressed at levels 3 to 7-fold higher in the daf-2 mutant compared to the WT and daf-2/daf-16 double mutants. The other three genes were downregulated in the daf-2 mutant in a DAF-16-dependent manner. Thus, DAF-16 can act as both a transcriptional activator and/or repressor depending on the gene context.

The next set of experiments involved the use of the RNAi method to reduce the expression of each candidate gene thereby determining which of them may be involved in daf-2 signaling. A complete nematode RNAi library available in Escherichia coli was used for this purpose. WT and daf-2 mutant worms were fed the RNAi-containing E. coli and effects on lifespan, fat storage, and dauer arrest in live animals were observed. Dr. Ruvkun and collaborators showed that changes to the lifespan of worms were elicited through RNA inactivation. Specifically, they found that if RNAi of rbp-2, the retinoblastoma binding protein-2 gene homolog, or the hpd-1 gene, the hydroxyphenylpyruvate dioxygenase homolog, was introduced into worms, their lifespan was increased by 30 percent. When RNAi of the DAF-2 parent receptor was fed to worms, lifespan was increased by 100 percent. These results indicated that rbp-2 and hpd-1 may constitute only a fraction of the daf-16 transcriptional cascade; many other transcriptional targets affected by the daf-2 signaling pathway may exist because only part of the signaling pathway was knocked out by feeding RNAi one at a time to worms.

Dr. McCormick discussed how these genes are related to control of gene expression, chromatin remodeling, and metabolism, specifically fat storage, metabolism, and biosynthesis. She concluded her presentation by stating that Dr. Ruvkun and collaborators have become some of the main contributors to the effort of deciphering the genetic basis of longevity by using new technologies, such as bioinformatics tools and RNAi. The application of these new technologies to studies of the basis of longevity, aging, and age-related diseases is expected to accelerate the pace of this and other related research.

In response to questions from Council members, Dr. McCormick stated that C. elegans are ideal for these experiments because they consume E. coli so they can be fed RNAi. In turn, the RNAi inhibit the translation of specific messages in the worm, the effects of which can be observed through changes in lifespan, fat storage, and dauer arrest. However, it will be very difficult to replicate this experiment in mammalian cells, particularly on a high through-put scale. She also mentioned that there are trade-offs between fertility and longevity when longer life is induced through these manipulations, but decreased fertility may not be the mechanism for increased longevity.

3. Geriatrics and Clinical Gerontology: B 12 Nutrition in the Aged

Dr. Sally P. Stabler, Professor of Medicine, Division of Hematology, University of Colorado School of Medicine began her presentation by describing the background of what was previously known about severe vitamin B 12 deficiency, resulting from pernicious anemia causing severe megaloblastic anemia and/or degeneration of the spinal cord nerves and brain. In the early 1980s it was thought that serum vitamin B 12 levels were very specific and sensitive for the diagnosis of deficiency. However, Dr. Stabler and her mentor, Dr. Robert Allen, developed new diagnostic methods for B 12 deficiency by analyzing the metabolites of the only two B 12 dependent enzymes. They showed that elevations of serum methylmalonic acid (MMA) and total homocysteine were very useful in demonstrating clinical vitamin deficiency and documenting response to therapy.

With the metabolites, Dr. Stabler had a tool to determine whether the decline in B 12 levels with age is actually a normal component of aging or a treatable vitamin deficiency. Her studies of various geriatric cohorts showed that there is a 10-20 percent prevalence of untreated vitamin B 12 deficiency in seniors and that a low vitamin B 12 level has only a 50 percent sensitivity and specificity. Elevated metabolite levels in seniors fall to normal after adequate vitamin B 12 and/or folate treatment.

Elevated homocysteine has been shown to be a potentially modifiable risk factor for vascular disease, cognition, and all-cause mortality. Recently grains have been supplemented with folic acid in the United States, which has decreased the prevalence of folate deficiency and hyperhomocysteinemia. Therefore, in order to determine how such fortification impacted homocysteine values in seniors, Dr. Stabler performed a study in collaboration with investigators in rural Georgia. These seniors receiving Title IIIC nutrition services (80 percent female, 32 percent African-American) had very high folate status but they did not have low homocysteine values because the prevalence of B 12 deficiency was high. Those with B 12 deficiency were 3 times more likely to score poorly on a cognition test.

The large number of seniors with vitamin B 12 deficiency presents a problem for treatment since standard monthly injections given by health care providers are expensive. High dose oral therapy was proven effective by Dr. Stabler and colleagues and she recently performed a treatment study to test lower oral B 12 doses. Surprisingly, she found that 100 mcg or less of oral B 12 was only effective in 30 percent of seniors. After 6 weeks of 1000 mcg, the other 70 percent of the group corrected elevated MMA. This proves that the commonly available multivitamins marketed to seniors will not be effective treatment for B 12 deficiency.

Dr. Stabler has developed sensitive assays for S-adenosylhomocysteine and S-adenosylmethionine, which are the precursors of homocysteine, and she will study these compounds in relation to the clinical syndromes of B 12 deficiency and hyperhomocysteinemia and the impact of renal insufficiency.

She concluded that in the United States, elevated homocysteine is most likely due to B 12 deficiency, therefore treatment directed towards hyperhomocysteinemia should either screen for vitamin B 12 deficiency or empirically treat with high dose vitamin B 12 as well as folic acid. This is particularly important in subjects with renal insufficiency who require high doses of folate, B 12 and B 6 to lower homocysteine.

4. Behavioral and Social Research: Informal Caregiving for Chronic Diseases in the Health and Retirement Study

Dr. Kenneth Langa, University of Michigan, shared results from his NIA-funded studies on informal caregiving, which he conducted with colleagues at the Institute for Social Research using data from the Health and Retirement Study (HRS). “Informal caregiving” is defined as help with daily activities that is provided by a relative or an unpaid non-relative.

It is not surprising that informal care is commonplace and time-consuming. Prior studies have found that approximately 23 percent of U.S. households contain a caregiver, which equates to approximately 26 million caregivers. Approximately three-quarters of these caregivers are women. More than a third of the caregivers provide more than 20 hours of care per week. It is clear from prior studies that providing high levels of care creates stress for the caregivers, and this can affect their health adversely. Caregivers may have higher rates of depression and anxiety, and even increased mortality. Providing more moderate levels of care might be beneficial to a caregiver's health, possibly because the emotional bond and feeling of usefulness may be salutary.

Dr. Langa observed that a confluence of demographic shifts, public policies, and market trends will affect caregiving over the next decade. These will include: the increasing number of elderly living in the community, the decreasing number of children available to care for aging “Baby Boomers,” more geographically dispersed families, changes in reimbursement and utilization of home care, and increases in alternatives to nursing homes. It is estimated that the economic value of care given to adults aged 18 and older is almost $200 billion a year, although Dr. Langa's studies have focused only upon the segment of adults who are age 70 and older.

Dr. Langa's studies used data from the Asset and Health Dynamics (AHEAD) Study, a subsample of the full HRS, which includes 7443 respondents aged 70 or older at the time of the baseline survey in 1993. In the AHEAD sample, 41 percent reported at least one ADL or IADL limitation. In terms of costs, approximately 26 percent of the sample received informal care, which comprises approximately two-thirds of all those who reported an ADL or IADL limitation. This represents 5.5 million individuals who currently are receiving informal care. On average, among those receiving care, approximately 26 hours of care per week were provided by informal caregivers. At a cost of $8.20 per hour of care, the annual informal caregiving cost estimated from the AHEAD data is $61 billion.

Dr. Langa next presented the impact of individual chronic diseases upon informal caregiving. Informal caregivers provide approximately three times the hours of care per week for stroke victims, compared to those without stroke, and approximately 60 percent more hours for persons taking insulin, compared to those with no diabetes. Urinary incontinence also is associated with significant amounts of informal caregiving, more so for men than for women. Finally, severe cognitive impairment is associated with the greatest level of informal caregiving, approximately 46 hours per week, compared to 5 hours per week for those scoring normal on the cognitive assessment.

Dr. Langa estimates that the additional annual cost of informal caregiving per person adds up to $1,700 for diabetes, $2,000 for urinary incontinence, $5,000 for stroke, and $17,000 for dementia. He estimates that the national annual cost of informal caregiving is $6 billion for diabetes, $6 billion for urinary incontinence, $6 billion for stroke, and $18 billion for dementia. Other work he is involved in suggests that caregiving for depression costs $9 billion annually.

There were also interesting gender differences in caregiving. Older disabled women are less likely than men to be married (28 percent vs. 74 percent), more likely to live alone (45 percent vs. 17 percent), and more likely to have low net worth (24 percent vs. 11 percent). Even when married, disabled women receive less care from their husbands than disabled men receive from their wives. Disabled women, therefore, receive significantly fewer hours of informal care than do men, even after adjusting for level of disability and age. For women who are living alone, it is most commonly their daughters who are providing care.

Dr. Langa concluded that informal caregiving for the chronic conditions of aging represents a significant time commitment for family members and a significant societal economic cost. Older women are likely to be at greater risk for unmet caregiving needs, since they are more likely to live alone; even when married, they receive significantly less care from family members. Evaluations of medical and public policy interventions need to account for the significant quantity of this off-budget informal caregiving, which does not appear on Medicare or other accounts.

Future directions of Dr. Langa's work include (1) studying the dementia supplement and the HRS' Aging, Demographics, and Memory Study (ADAMS); (2) looking at longitudinal economic and health outcomes for caregivers, particularly as chronic diseases progress and individuals die; and (3) tracking caregivers' movements during the day through “experience sampling,” using Palm pilots.

7. Adjournment

The 89th meeting of the National Advisory Council on Aging was adjourned at 1:38 p.m. on May 21, 2003. Dr. Hodes closed the Council session by thanking all speakers and the Council members for meeting, and exceeding, the Council's high standards. The next meeting is scheduled for September 23-24, 2003.

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. with assistance from the Constella Group, Inc.

Attachment A

MEMBERSHIP ROSTER
NATIONAL ADVISORY COUNCIL ON AGING
NATIONAL INSTITUTE ON AGING

(All terms end December 31) (†Terms extended until June 30, 2003) (*WGoP member)

Chairperson

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

Dennis A. Ausiello, M.D. (2003)
Chief, Medical Services
Massachusetts General Hospital
Boston, MA 02114

Marie A. Bernard, M.D. (2005)
Donald W. Reynolds Chair
Donald W. Reynolds Dept of Geriatric Medicine
University of Oklahoma College of Medicine
Oklahoma City, OK

John C. Cambier, Ph.D. (2003)
Ida and Cecil Green Professor and
Chairman, Integrated Dept. of Immunology
National Jewish Medical & Research Center
and Univ. of Colorado Health Sciences Ctr
Denver, CO 80206

†Judith Campisi, Ph.D. (2002)
Senior Scientist
Division of Cell and Molecular Biology
Lawrence Berkeley Laboratory
University of California
Berkeley, CA 94720

†Rose W. Dobrof, DSW (2002)
Brookdale Professor of Gerontology
Brookdale Center on Aging
Hunter College of the City of New York
New York, NY 10036

*David V. Espino, M.D. (2004)
Professor
Dept of Family & Community Medicine
Division of Community Geriatrics
University of Texas Health Science Center
San Antonio, Texas 78229-3900

F. Michael Gloth, III, M.D. (2005)
President
Victory Springs Senior Health Care
Reisterstown, MD 21136

Eugene M. Johnson, Jr., Ph.D. (2005)
Norman J. Stupp Professor, Department of
Neurology
Professor, Dept. of Molecular Biology and Pharmacology
Co-Director, Alzheimer's Disease Research Center
Washington University School of Medicine
St. Louis, MO 63110

*Lewis H. Kuller, M.D., DrPH, MPH (2004)
Professor and Chairman
Department of Epidemiology
Graduate School of Public Health
University of Pittsburgh
Pittsburgh, PA 15261

Ronald D. Lee, Ph.D. (2005)
Professor, Department of Demography
College of Letters and Science
University of California
Berkeley, CA 94720-2120

Peter W. Nauert, J.D. (2005)
Principal
Insurance Capital Management
Chicago, IL 60606

Stanley B. Prusiner, M.D. (2004)
Director and Professor
Institute for Neurodegenerative Diseases
School of Medicine
University of California
San Francisco, CA 94143-0518

*Judith A. Riggs, M.A. (2004)
Washington, DC 20016

*Ilene C. Siegler, Ph.D. (2003)
Professor of Medical Psychology
Dept of Psychiatry & Behavioral Sciences
Duke University
Durham, NC 27705

Leon J. Thal, M.D. (2005)
Professor and Chair
Department of Neurosciences
University of California San Diego
School of Medicine
La Jolla, CA 92093-0624

†Myron L. Weisfeldt, M.D. (2002)
William Osler Professor of Medicine
Director, Department of Medicine
Johns Hopkins University School of Medicine
Baltimore, MD 21287

† David A. Wise, Ph.D. (2002)
Professor
National Bureau of Economic Research
Cambridge, MA 02138

*Phyllis M. Wise, Ph.D. (2003)
Dean, Division of Biological Sciences
University of California Davis
Davis, CA 95616-8536

Ex Officio Members

Tommy G. Thompson
Secretary
Department of Health and Human Services
Hubert H. Humphrey Building
Washington, D.C. 20202
Elias Zerhouni, M.D.
Director, National Institutes of Health
Public Health Service Bethesda, Maryland 20892-0148

James F. Burris, M.D.
Deputy Chief Research and Development Officer
Office of Research and Development
Department of Veterans Affairs
Washington, D.C. 20420

Colonel George F. Fuller, M.D.
USUHS
Department of Family Medicine (FAP)
Bethesda, MD 20814-4799

John Wren
Director, Office of Program Development
Administration on Aging, DHHS
Washington, D.C. 20201

[ 1 ], [ 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 23-24, 2003, and corrections or notations will be stated in the minutes of that meeting.