The 105th Meeting
September 24–25, 2008
- REVIEW OF APPLICATIONS
- CALL TO ORDER
- REPORT: Task Force on Minority Aging Research
- REPORT: Working Group on Program
- REPORT: Council of Councils
- INITIAL REPORT: Division of Behavioral and Social Research Review
- REPORT: Division of Neuroscience Review
- PRESENTATION: Clinical and Translational Science Awards—Clinical Research in a Cost-Effective Environment
- DIVISION HIGHLIGHTS
The 105th meeting of the National Advisory Council on Aging was convened on Wednesday, September 24, at 3 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 Wednesday, September 24, from 3 p.m. to 5 p.m. for the review, discussion, and evaluation of grant applications and on Thursday, September 25, from 2:05 to 2:45 p.m., for Council review of the subcommittee report on the Scientific Director 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 Thursday, September 25, from 8 a.m. to 2 p.m.
Dr. Dale E. Bredesen
Dr. Kenneth V. Brummel-Smith
Dr. Peggye Dilworth-Anderson
Dr. Carl Eisdorfer
Dr. Lawrence M. Friedman
Dr. Mary Ganguli
Dr. S. Michal Jazwinski
Dr. Sundeep Khosla
Dr. Terry L. Mills
Dr. John C. Morris
Ms. Orien Reid
Dr. Gerald P. Schatten
Dr. Albert L. Siu
Dr. Susan L. Swain
Dr. Mary E. Tinetti
Dr. Paul Greengard
Dr. James Burris, Department of Veterans Affairs
Ms. Lori Gerhard (Alternate), Administration on Aging, U.S. Department of Health and Human Services
Dr. Kenneth Pugh, National Naval Medical Center
The Council Roster, which gives titles, affiliations, and terms of appointment, is appended to these minutes as attachment A.
In Addition to NIA Staff, Other Federal Employees Present:
Dr. Rene Etcheberrigaray, Center for Scientific Review, NIH
Mr. Donald Grantt, Administration on Aging
Ms. Denise Manouelian, National Institute of Diabetes and Digestive and Kidney Diseases, NIH
Dr. Iris Obrams, National Center for Research Resources (NCRR), NIH
Ms. Shelly Pollard, NCRR, NIH
Members of the Public Present:
Dr. Susan Diem, University of Minnesota
Ms. Ann Elderkin, American Society for Bone and Mineral Research
Dr. Desmond Fitzgerald, University College at Dublin
Dr. Frances McFarland-Horne, Rose Li and Associates, Inc.
Dr. Gerald Karsenty, Columbia University
Ms. Patricia Kobor, American Psychological Association
Dr. Kenneth Langa, University of Michigan
Dr. Rose Li, Rose Li and Associates, Inc.
Dr. Eric Orwoll, Oregon Health and Science University
Ms. Amy Pollick, Association for Psychological Science
Mr. Roland Weeks, MasiMax Resources
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 552(b)(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 947 applications requesting $1,184,826,143 for all years underwent initial review. The Council recommended 484 awards for a total of $879,837,583 for all years. The actual funding of the awards recommended is determined by the availability of funds, percentile ranks, priority scores, and program relevance.
Dr. Hodes welcomed members to the open session of the 105th National Advisory Council on Aging meeting and called the meeting to order at 8:05 a.m. on Thursday, September 25, 2008.
Dr. Hodes announced that Dr. Elias Zerhouni, NIH Director, is resigning at the end of October and that the transitional leadership has not yet been announced. He acknowledged Dr. Zerhouni’s many accomplishments. Dr. Hodes also reminded the Council that Dr. Marie Bernard will join the NIA in October as Deputy Director, and he thanked Dr. J. Taylor Harden for her work as Acting Deputy Director.
Dr. Robin Barr introduced Dr. Chyren Hunter, new Deputy Director of the Office of Extramural Activities, and announced that Dr. Andrew Monjan will be retiring from the Division of Neuroscience. Dr. Richard Suzman introduced Ms. Jillian Angelo, a new extramural program office manager in the Division of Behavioral and Social Research (BSR). He also acknowledged Professor Desmond Fitzgerald, of University College at Dublin, who was visiting. Ms. Charlene Liggins, a new scientific program analyst in the Office of Planning Analysis and Evaluation; Ms. Andrea Griffin-Mann, a new program analyst in the Office of the Director; and Dr. Jeannette Johnson, of the Scientific Review Branch, were also introduced.
B. Director’s Status Report
Dr. Hodes discussed recent activities in the NIH effort to enhance peer review. From June 2007 to February 2008, the NIH conducted a diagnostic process to provide opportunities for input, which led to a design and implementation plan with three priorities.
The first priority involves engaging the best reviewers. The NIH aims to improve reviewer retention; for example, by providing new reviewers some flexibility through shared responsibility or less than full-time commitment and through virtual reviews. In addition, a toolkit incorporating best practices for recruiting reviewers will be made available to Institutes and Centers (ICs) in 2009. Dr. Hodes also mentioned efforts to improve reviewer training, which normally occurs through ad hoc appointments or additional appointments to other study sections.
The second priority involves improving the quality and transparency of the review itself. For example, beginning with applications reviewed in May 2009, scoring will change to a scale of 1 to 7, and reviewers will provide feedback through scores and through critiques for each criterion in a structured summary statement. Applications also will be shortened and streamlined, reducing the focus on details that detract from the overall review. These streamlined applications will align with review criteria for the January 2010 receipt dates.
The third priority involves reducing administrative burden and ensuring balanced and fair reviews across scientific fields and career stages. Dr. Hodes discussed the increased burden on applicants, reviewers, and NIH staff resulting from a recycling of applications for re-review. Since 2003, the percentage of total awards arising from A0 (new) applications has declined precipitously, while that arising from A1 and A2 applications has risen, potentially reflecting improvement in the quality of applications as a result of review and revision, but perhaps more likely because reviewers are inclined to give better scores to A2 applications because this is recognized as the last chance for funding. The concern is then that outstanding research is delayed substantially, and the review burden is increased. To discourage this behavior, the NIH is considering the elimination of A2 applications. (Following Council a Notice was published in the NIH Guide on October 10, 2008, announcing that A2 applications would no longer be accepted for new or competing renewal applications beginning on January 26, 2009.)
The NIH (also) is establishing an Early-Stage Investigator (ESI) designation, as many investigators previously classified as “new investigators,” and who therefore received preferential treatment directed to this group of applicants, are not in the early stages of their careers. “New investigator” is defined as one who has no previous history of R01 funding or equivalent from the NIH, and ESI is defined as a new investigator who is within 10 years following doctoral training for Ph.D.s or clinical training for M.D.s. In 2009, the NIH will evaluate the clustering of ESI applications for review. A similar approach will be considered for clinical research applications.
Dr. Hodes then discussed the NIA budget. He reminded the Council that, following a peak in 2003, the NIH has steadily seen an erosion in buying power, resulting in a cumulative decrease of about 13 percent. As of September 24, 2008, a continuing resolution is in place in which all nonmilitary components of the Federal Government will be funded at 2008 levels through March 2009. It is likely that the fiscal year (FY) 2009 budget will look similar to that for FY08. Dr. Hodes reviewed data concerning the success rates for funding from the NIA and NIH overall from 2004 to 2008. For most funding mechanisms, the success rates have remained flat. The P01 mechanism appears to have a better success rate than other mechanisms, although it too has declined during the past 4 years. Dr. Hodes noted that, even with special considerations, the success rate is still lower for new as opposed to established investigators. However, he also pointed out that the difference compared with all investigators is somewhat lower than it would be if no special considerations were given.
The NIH Research, Condition, and Disease Categorization (RCDC) Project, an effort to make the categorization and reporting of research funding transparent, uniform, and automated, is moving forward. This system will become the major means by which the public will gain access to NIH funding information by disease, condition, and life stage. An analysis based on categorizations established in 2008 is expected to be completed by November, and a report will be generated by January 2009 and posted on the Web by February 2009, in time for the springtime appropriation hearings in Congress. This report will present data for 2007 and 2008. The 2007 data will be reported both through RCDC and the old system to allow side-by-side comparisons. The initial online RCDC report will cover 215 categories, and each category will have 2008 project listings including title, principal investigator, institution, State, and funding amounts. Dr. Hodes speculated that the funding reported for each category is likely to change with the move to the new system because of differences in definitions. The entire NIA portfolio will be included in the “Aging-Closely Related” category. Dr. Hodes explained that the Aging research category will also include projects from other ICs. He also stressed the difficulties in using machine-based algorithms to replicate human judgment that can better account for research context. It is important to emphasize that RCDC will not change the grant application or review process but will inform future NIH scientific planning and evaluation.
Dr. Kenneth Brummel-Smith asked whether the RCDC system will allow for categorization around aging-related function. He noted the common disconnect between disease-based thinking and function in terms of activities of daily or independent living. Dr. Hodes responded that the initial categories were driven by requirements for reporting to Congress. However, the aging category does include issues of function, as identified by the experts in developing the aging research algorithms. Dr. Lis Nielsen added that RCDC also includes other research categories that are not disease-specific such as behavioral and social science.
C. Future Meeting Dates
January 27–28, 2009 (Tuesday and Wednesday)
May 19–20, 2009 (Tuesday and Wednesday)
September 22–23, 2009 (Tuesday and Wednesday)
D. Consideration of the Minutes of the Last Meeting
The minutes of the May 2008 meeting were considered. A motion was made, seconded, and passed to approve the minutes.
E. NIA Statistical Package
Dr. Barr reported that NIA applications in peer review have distributed along the expected path for success rates. By way of response to questions from Dr. Gerald Schatten, Dr. Barr will provide the Council with a comparison of success rates by division for multiple years.
F. Comments from Retiring Members
Dr. Hodes recognized four outgoing Council members and presented them with certificates: Dr. Paul Greengard, Dr. Terry Mills, Dr. Albert Siu, and Dr. Mary Tinetti.
Dr. Greengard was not at the meeting, but he sent forward his comments acknowledging the quality of NIA staff, the integrity of the review process, and the dedication the Council shows to achieving the highest level of accomplishment. He expressed his regrets at not being able to attend today’s meeting, but he noted that he had enjoyed working with everyone.
Dr. Mills was recognized by Dr. Hodes for his role in leading the Task Force on Minority Aging Research and for his contributions to all the Council’s deliberations. Dr. Hodes pointed out that Dr. Mills’ work on the Task Force has led to concrete evidence of advances and innovations that will make a difference. Dr. Mills stated that it had been an honor and privilege to serve on the Council, and he acknowledged the accomplishments and effort of his colleagues. He noted the mutual respect among Council members and described his service as an interdisciplinary training experience in which he learned not only about the workings of the NIA and its programs but also about scientific topics such as the molecular biology of Alzheimer’s disease (AD).
Dr. Hodes recognized Dr. Siu’s push for active interchange involving mutual respect and interrogating issues from a scientific perspective. Dr. Hodes also acknowledged that Dr. Siu had brought to the fore areas in which the NIA had allowed convention, practice, and presumption to drive its decisionmaking, and that, as a result, the NIA has become more vigilant. Dr. Siu stated that it had been a privilege working with the Council, and he especially acknowledged his fellow retiring members. He noted the amount of time it takes to learn how to be a Council member, and he noted that he had been gratified by the NIA leadership’s response to issues raised by the Council. For example, it responded positively to the Council’s desire to know more about set-asides so it could effectively carry out its role. Dr. Siu pointed out that he had already known the leadership in the Division of Geriatrics and Clinical Gerontology but that, as a result of his service on the Council, he had also had the privilege of getting to know the leadership at other NIA divisions. Finally, he noted the efficiency with which the NIA continued to function even when key figures departed from its staff.
Dr. Tinetti was absent from today’s meeting.
Dr. Terry Mills reminded Council that one research goal in the NIA Strategic Plan is “to improve our ability to reduce health disparities and eliminate health inequities among older adults and populations.” Accordingly, Task Force discussions over the last several Council meetings have examined ways that NIA, NACA, and the research community can achieve this goal.
In its most recent meeting, the Task Force heard from Dr. Peggye Dilworth-Anderson, who discussed an International Conference on Alzheimer’s Disease preconference that she organized with Dr. Nina Silverberg entitled “Strengthening Alzheimer’s Research in Diverse Populations.” The goal of this preconference was to find ways to engage people in the community and identify how best to link research with a community in which AD is stigmatized. Preconference presentation topics included approaches used to recruit and retain diverse groups; education; health literacy and bilingualism; postmortem research; and recruitment for genetic studies on AD.
The preconference also included a presentation on community-based participatory research (CBPR). With this approach, researchers focus on a topic of importance to the community; the ultimate aim of this approach is to combine knowledge and actions for social change to improve community health and eliminate health disparities. The key elements of CBPR include recognizing the community as a unit of identity, using and building upon the community’s strengths and resources, making mutual benefits available to all partners, establishing and sustaining community partnerships, empowering the community and working toward addressing social inequities, and disseminating study findings to the community. Dr. Mills highlighted several effective recruitment strategies used in CBPR and the importance of these strategies in light of minorities’ distrust of the medical profession in the aftermath of the Tuskegee experiments and other medical atrocities. The preconference drew several conclusions. Recruitment efforts were varied and included both traditional and unconventional strategies and tactics, and recruitment was focused in places that reflected the demographic profile of the target population. Ongoing relationships were established with community-based organizations and agencies, and incentives were used to better assure participation. By using these strategies, researchers were able to reduce barriers to participation.
Dr. Mills reported on a second presentation to the Task Force by Dr. Joyce Hunter, Deputy Director of the National Center on Minority Health and Health Disparities (NCMHD). Dr. Hunter described several NCMHD initiatives, including one on the Research Endowment Program, which promotes the education and training of underrepresented minority and socioeconomically disadvantaged individuals by awarding grants to eligible institutions. Funding for these grants, which ranges from $300,000 to $5 million, represents an investment, and returns on this investment are key to the success of the program. An NCMHD-sponsored summit, “The Science of Eliminating Health Disparities,” is scheduled for December 16–18, 2008, at the Gaylord National Resort and Conference Center in National Harbor, MD.
Finally, the Task Force discussed the Health Disparities Resource Persons Network, an NIA-established Web-based resource consisting of research professionals in aging, geriatrics and gerontology who volunteer their services in support of research and the NIA’s goals to redress health disparities and to improve the health status of racial, ethnic, and disadvantaged older adults. Dr. Mills reminded the Council that the Task Force had previously discussed the importance of expanding this scientific network to include individuals who are interested or have specific expertise in minority health issues. The resource will become active October 1. Dr. Mills stressed the importance of ensuring this resource’s success.
Dr. Morris reported on a presentation by Dr. Suzana Petanceska, who discussed a Division of Neuroscience (DN) workshop on the role of Apolipoprotein E (ApoE) in normal brain aging and AD. He noted that, 15 years after its discovery, ApoE is still the most significant AD risk factor identified to date, but how it is involved in mechanisms of cholesterol regulation, cognitive aging, or neurodegenerative processes is still poorly understood. ApoE appears to influence cognition throughout the lifespan, even from early ages, and it appears to influence AD pathogenesis through both dependent and independent mechanisms. However, there are exceptions; for example, it appears that ApoE4 does not confer risk for AD among the Yoruba tribe of Nigeria.
Workshop recommendations for future research directions with regard to ApoE include increasing understanding of aging-related changes in lipid homeostasis in the central nervous system and in different paradigms of neurodegeneration, interrogating the role of ApoE and its receptors in normal brain aging, and identifying isoform-specific differences in ApoE function. Other recommended future directions include application of a lifecourse approach and study of the role of ApoE during brain development, particularly during critical periods in cognitive development, and understanding how genetic and environmental factors interact in different populations to modulate the negative effects of the ApoE E4 alleles on brain. In conclusion, workshop participants recommended that the NIA invest more in stimulating research on ApoE and lipid neurobiology as they relate to aging and AD.
A motion by NACA to approve the workshop recommendations was forwarded, seconded, and passed unanimously.
Ms. Orien Reid, who represents NACA on the NIH Council of Councils (COC), reported on recent COC activities. The COC membership represents the 27 ICs and specialized NIH offices. Its role is to advise the NIH Director on policies and activities and make recommendations on trans-NIH research supported by the Common Fund. At its March 31–April 1, 2008, meeting, Dr. Zerhouni stressed the importance of COC members serving as liaisons to their respective advisory councils and of open, transparent, and bidirectional communication between the COC and individual advisory councils. Dr. Zerhouni challenged the COC to assess the current scientific frontiers and to promote high-risk ideas. He also noted that the COC is in a high-profile position and is expected to have a large impact; additionally, there is widespread interest in the COC’s activities.
The COC has aligned itself with the three divisions of the Office of Portfolio Analysis and Strategic Initiatives (OPASI), establishing subcommittees in Resource Development and Analysis, Strategic Coordination, and Evaluation and Systematic Assessments. Ms. Reid serves on the subcommittee for Resource Development and Analysis. She reported that the subcommittee has tested the RCDC and recalled Dr. Tim Hays ’ presentation about the RCDC Program at the May NACA meeting.
Ms. Reid also highlighted several presentations at the most recent COC meeting. Dr. Lawrence Tabak discussed interdisciplinary research and its challenges; he particularly stressed that interdisciplinary research does not necessarily equate with team science. Dr. Francis Collins reported on the Molecular Libraries Roadmap Initiative, which combines chemistry and biology. This initiative, the largest Roadmap initiative so far, is almost at the end of its pilot phase and is undergoing peer review. Dr. Elizabeth Wilder discussed an NIH retreat where upcoming initiatives for FY09 –10 were reviewed. Dr. Barbara Mittleman discussed public-private partnerships, another way for the NIH to leverage resources and create synergy, and Ms. Amy Porter and Ms. Julie Wolf-Rodda discussed the Foundation of the NIH, which allows the expansion of the number of funded grants through funds from other agencies. The working groups responsible for testing the RCDC system also presented at this meeting.
The next COC meeting will be held November 20 –21, 2008, and will focus on obesity. The meeting will include reports on the NIH Obesity Research Task Force, the role of OPASI in trans-NIH obesity and nutrition research, the burden of obesity-related disease, and the nutrition biome. The Working Group on the Science of Science Management also will make a presentation, and the COC will approve concepts for trans-NIH Roadmap initiatives. Dr. Hodes emphasized the interactions among ICs, their advisory councils, and the COC and the importance of these interactions in keeping all informed.
Dr. Sundeep Khosla noted the larger emphasis on translational research and clinical trials within NIH and asked whether leadership is considering integrating multiple ICs in large clinical trials involving multiple end points. Ms. Reid responded that she would take the question back to the COC. Dr. Hodes noted that collaborations centered around the Common Fund are clearly authorized in the budget but that the Fund is intended to be an incubator for innovative research, not for long-term or continuous activities. Thus, he thinks it unlikely in the immediate future that a large-scale clinical trial would be supported by the Common Fund. Dr. Hodes also noted that institutions proposing an initiative should be able to see what is happening and what is being planned in other ICs and post an early alert to allow other ICs to participate in planning the initiative. Dr. Mary Ganguli suggested that NIA leadership work with media to promote research participation among citizens. She also suggested that the COC look into developing a public service announcement as a way to change people’s perceptions of clinical research. Ms. Reid appreciated the idea and noted that, although this might be a long-term possibility, it likely would not be something that is addressed initially. Dr. Hodes added that offices of public communication at each IC and the NIH are paying attention to this issue, and he noted that the NIH Director’s Council of Public Representatives is discussing it.
Dr. Morris reported on the NACA review of BSR, which was co-chaired by Dr. John Cacioppo and Dr. Alan Garber. In his presentation to the Working Group on Program the day prior, Dr. Garber praised the helpfulness, responsiveness, and commitment of BSR staff and acknowledged the coordination provided by Rose Li and Associates, Inc. The Review Committee, which included 16 distinguished experts in the field of behavioral and social research, was charged with answering questions under the following five major areas:
- What promising areas for future research should BSR be encouraging?
- Has BSR been supporting a balanced, high-quality, and innovative portfolio of research? Are there significant gaps? What areas are weaker than they should be, and which, if any, might not be deemphasized?
- Is the branch structure appropriate to the science? Is BSR adequately staffed?
- How can BSR promote training and development of new scholars in fields that are becoming increasingly interdisciplinary? Is BSR attracting adequate numbers of high-quality individuals to pursue research careers in fields of relevance to BSR, and can their professional development be sustained?
- What can be done to ensure appropriate review of high-risk, interdisciplinary research projects and program projects?
The Review Committee held teleconferences on May 12, July 29, and September 4, 2008, and held a face-to-face meeting on September 22–23, 2008. Nine subcommittees also held meetings and invited comment in detailed reviews of scientific topic areas. These meetings resulted in the generation of a preliminary report with the following overarching recommendations:
- Support the principle of identifying and supporting work of highest scientific merit rather than research that focuses on narrow questions lacking general interest.
- Continue to emphasize integrative science and multilevel analyses.
- Adopt a lifecourse perspective.
- Consider establishing a board to advise BSR on how to prioritize intervention and translation projects.
- Revitalize social demography, epidemiology, and sociology portfolios.
- Support theoretically informed disparities research.
- Provide training support.
- Develop appropriate datasets, and continue to work to support data availability.
The Review Committee will work between September and December to complete the report, which will be presented for approval at the January 2009 Council meeting.
Dr. Morris noted concern about the lack of senior reviewers in the peer-review process. It appears that fewer senior researchers in behavioral and social research are willing to serve on review panels, raising questions about the quality of these reviews. Dr. Garber suggested new initiatives in the overall peer-review system that may alleviate this problem.
Dr. Barr asked for clarification on the recommendation about supporting research of the highest scientific merit. He indicated that the NIA already funds applications up to the tenth percentile. Dr. Morris responded that there should be a bottom-up approach, with applications from investigators being used to delineate areas of greatest interest. Dr. Suzman added that in response to a similar question, Dr. Garber had clarified the day before that the Review Committee’s recommendation was meant to help BSR discriminate among projects it should support in the health services area. Dr. Mills expressed support for a combination of bottom-up and top-down approaches, noting that areas of interest usually come from investigators but that BSR can identify areas that need support and strengthening. Dr. Hodes added that initiatives arising from workshops are essentially set by NIA as institution-directed initiatives. He noted, however, that NIA program staff also build programs primarily through investigator-initiated research, and their efforts in encouraging the establishment of new areas do not receive enough credit. Dr. Hodes pointed out that the NIA has a responsibility to let researchers know what the science of relevance is. Dr. Morris will suggest that the Review Committee clarify this recommendation.
Dr. Hodes expressed appreciation for the review and emphasized the value of such a comprehensive and effective review as this. He noted that these efforts provide NIA with an overview of its portfolio and complement the efforts of NACA in reviewing individual applications and requests for applications (RFAs).
Dr. Morris presented the official report arising from the review of DN. He reminded Council that the goals of the review were to evaluate the quality, appropriateness, and balance of the extramural research portfolio and to evaluate the Division’s ability to respond to new research opportunities. This review panel also formed several working groups. The review process included meetings with program staff, an examination of material provided, and a series of conference calls and face-to-face meetings from February through May and then submission of final workgroup reports following the May Council meeting.
The review panel made the following conclusions:
- The DN is addressing appropriate scientific areas.
- The investigator-initiated or “bottom-up” approach to drive science is effective and sound.
- Diversity initiatives and succession planning are in place.
- Dr. Morrison-Bogorad; Branch Chiefs Dr. Buckholtz, Dr. Monjan, and Dr. Wagster; and the entire program staff are outstanding.
Dr. Morris also highlighted specific recommendations by the Review Committee:
- Develop a process to revise clinical diagnostic criteria for AD.
- Support imaging modalities, biomarkers, and improved cognitive measures.
- Support emerging fields, such as epigenetics, drug discovery, and neural plasticity and repair.
- Establish a Translational Research Section to streamline the development of promising drugs; this Section and DN as a whole should promote collaborations.
- Support longitudinal cohorts.
- Educate Special Emphasis Panels about AD centers and the AD Neuroimaging Initiative.
Dr. Khosla noted the overall pool of AD research supported by NIH and asked what proportion of it is supported by NIA versus the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute of Mental Health (NIMH). Dr. Morris responded that the majority of this research is supported by NIA and DN and that he does not know enough about the focus of non-NIA–supported research. Dr. Marcelle Morrison-Bogorad added that it is difficult to determine where the distinctions are with respect to research supported by NIA and that supported by NINDS, as both Institutes support basic research. Distinctions are much easier with respect to research supported by NIMH, which tends to focus more on the relationship between AD and depression.
Dr. Khosla asked whether this is an area ripe for more trans-NIH interchange and collaboration. Dr. Morris responded that such efforts are already underway. For example, NINDS is supporting a meeting on epilepsy and neurodegenerative diseases in which DN is participating. Dr. Morrison-Bogorad commented that an inter-Institute working group is in place and that ICs work together to develop conferences throughout the year. Dr. Hodes added that the NIH Blueprint for Neuroscience Research, a cooperative effort that involves all IC Directors and staff who coordinate neuroscience research, meets monthly and works on cofunding and planning for areas of overlap. Discussions have focused on themes such as neurodegeneration and neural plasticity, and a proposal has been made for longitudinal studies of normal aging. This latter effort involves the contributions of six ICs other than the NIA.
Dr. Brummel-Smith, referring to the Review Committee’s recommendation that NIA should work with other ICs to revise diagnostic criteria for AD, suggested that NIA also work with agencies outside NIH. Dr. Morris responded that the Alzheimer’s Association and other organizations will be part of the planning process.
A motion to accept this report as recommendations from NACA to NIA was forwarded and seconded. The motion was unanimously approved.
Dr. Eric Orwoll, of the Oregon Health and Science University (OHSU), provided an overview of the NIH Clinical and Translational Science Award (CTSA) program and then described his experience at the Oregon Clinical and Translational Research Institute (OCTRI). The NIH CTSA program, which now comprises 38 centers, is a large and ambitious program with the goal of building clinical and translational resources at academic health centers. Most CTSA awardees intend to grow the clinical and translational research enterprise at their institutions by building collaborations and funding pilot projects, among other activities.
At the institutional level, each CTSA program is oriented around an academic health center. That “home” incorporates various resources, including research, biostatistics, informatics, the old General Clinical Research Centers (GCRCs), education, and research ethics. Although the programs differ across institutions, they tend to be organized in similar ways, and they create opportunities for partnerships and collaborations with Government, industry, healthcare, and community organizations.
At the national level, the CTSA awardees form a consortium with several layers of organization. The National Center for Research Resources (NCRR) and the principal investigators of each CTSA provide oversight, with the help of several steering committees, each of which comprises several working groups. Dr. Orwoll noted that the organization of the consortium is a work in progress and must address the challenges of adding new centers each year. CTSA principal investigators serve as liaisons to the ICs to increase awareness of the resources available to IC-funded researchers, thus improving the efficiency of all aspects of clinical and translational science and maximizing the trans-NIH investments in core resources. Dr. Orwoll invited Council members to visit the CTSA Web site at www.ctsacentral.org.
Networks of CTSA programs, organized by region, are emerging to link national activities to the on-the-ground activities of the academic health centers. CTSA institutions on the West Coast appear to be the most organized. The West Coast network holds three regional meetings per year and has its own set of workgroups. The national CTSA Consortium is maturing, as reflected in its formal strategic planning process. Primary objectives of the national CTSA program, each with important implications for NIA-funded research, include the following:
- Develop a proof-of-principle approach through several clear examples of networks for enrollment and conduct of clinical trials that eventually could make the CTSA Consortium a “network of networks,” each focused on particular diseases and conditions but also linked by common data systems and informatics.
- Develop a national system of electronic data management and data sharing complemented by information technology tools.
- Develop a national biobank.
- Develop a national phenotyping system.
- Develop an effective national model for community engagement.
- Develop a clear-cut conflict-of-interest policy.
- Support regional and national healthcare reform.
- Develop a coordinated national comparative animal model core and tissue biorepository.
Dr. Orwoll went on to share the experience of the OCTRI. Before the CTSA award, clinical and translational science at OHSU had no formal structure. Since the award, OCTRI has been established as the CTSA home. OCTRI is a partnership between OHSU and the Kaiser Center for Health Research. OHSU provides a strong foundation in basic and clinical research and has a large tertiary referral population, while Kaiser offers many opportunities in population science, a large and representative community population, and a portal to other large patient populations. Although merging these institutions has been challenging, efforts are starting to pay off in terms of the science. Similar to other CTSA programs, OCTRI places a strong emphasis on communication, arrays programs in the service of investigators, and educates the next generation of clinical researchers and facilitates their transition to independence. Its vigorous clinical and translational research education program serves 60 trainees per year.
OCTRI also aims to improve clinical research infrastructure, enhance and support science by assembling interdisciplinary teams, forge public and private partnerships, and enhance public trust in research. Collaboration building is at the heart of OCTRI. For example, the program has used existing social networking software and is developing its own to bring together investigators from different disciplines. The School of Medicine has the authority for administration, support, and planning of clinical and translational research. A compliance interface has been established, including the creation of a shared electronic institutional review board (IRB) process with Kaiser, and this interface allows investigators to submit protocols and receive one set of comments and one approval. OCTRI has a Clinical Trials Office, has formed a partnership with the OHSU Cancer Center, and has a platform for clinical phases of collaborations with industry that serves as an outlet for public-private partnerships.
OHSU holds a variety of NIA awards spanning several mechanisms, including R01 grants, MERIT awards, a Roybal Center award, and an AD Center award. Kaiser holds additional NIA awards, serving as a site in the Women’s Health Initiative and conducting several subprojects. NIA investigators at each institution have access to OCTRI infrastructure and programs. OCTRI bears the cost of the research when the project is conducted by new investigators, defined as first-time R01 awardees, K awardees, or medical students. OCTRI also bears the cost when the projects are pilot projects or establish new directions in clinical and translational research. If the project is already funded by another NIH grant, the use of OCTRI resources is expected to be covered by project budgets. However, OCTRI has pledged both to investigators and to ICs that these expenses will be at cost.
Dr. Orwoll provided several examples of interactions between NIA-funded investigators and OCTRI, including (1) support to establish laboratories and translational collaborations to investigate the basic neuroscience of posture; (2) a symposia and shared pilot projects among OCTRI and primate center investigator; (3) an AD screening project; and (4) OCTRI’s health maintenance organization resource network, a virtual data warehouse that allows investigators to search for diagnoses, laboratory results, and other information. OCTRI has recently formed partnerships with the newly funded CTSA at The Scripps Research Institute to examine the genetics of healthy aging and has a shared pilot project program with Intel to further regional biotechnology efforts. OHSU intends for OCTRI to form a partnership with its Roybal Center to expand the community laboratory and may seek additional funding to expand the technology used to remotely monitor aging in the home.
Although OCTRI and CTSAs overall have made great strides, they still face several challenges. One is an inadequate budget to accomplish their goals. Identifying and achieving meaningful community engagement is another challenge, as are mentoring trainees with respect to post-K12 awards in the current funding climate and variability in institutional rules for additional K-mechanism support. Moreover, CTSAs face the possibility of principal investigator burnout, which arises from the intensity and complexity of leadership responsibilities at the local and national level.
Dr. Orwoll concluded his presentation by highlighting other ways CTSAs can form partnerships with NIA. He suggested discussions about local NIA portfolios that could reveal opportunities for future collaborations and linkages with special resources such as AD, Pepper, Roybal, and Primate Centers; identification of specific opportunities for training of geriatrics investigators that could be fostered by collaborations with CTSA certificate, training (T), and career development (K) programs; and an emphasis on enhancing opportunities for new aging investigators in their transition to independent research.
Dr. Brummel-Smith asked about the CTSA Consortium’s goals with respect to regulatory support and healthcare reform. Dr. Orwoll responded that the regulatory burden faced by investigators and institutions is a major impediment to the goal of speeding research. The national CTSA agenda includes a strong expectation that each CTSA program will establish mechanisms to monitor the success of IRB approval processes. These efforts, in addition to other efforts to work with national agencies, aim to transform IRB expectations. Local efforts include working with investigators to prepare for IRB review. With respect to transforming healthcare, Dr. Orwoll stated that he is not sure how that would occur, but he emphasized that this issue has emerged as a CTSA priority. This priority reflects an interest in community engagement and in the delivery of healthcare advances to a complicated system. Dr. Orwoll also emphasized that the CTSA program does not aim to become another bureaucracy.
Dr. Eisdorfer asked how OCTRI determines who receives support for pilot studies. Dr. Orwoll responded that OCTRI has a formal RFA mechanism, which offers RFAs tailored to clinical and translational research once or twice a year. A scientific committee reviews projects and scores them, similar to an NIH study section; a council reviews them; and awards are made. However, not all potential projects must undergo the scientific review—program staff can decide how to support some projects in the context of costs and CTSA priorities.
Dr. Hodes asked others whose institutions have CTSA awards how their experiences compared with those at OHSU. Dr. Khosla noted that the experiences at Mayo Clinic are similar, although the strengths and challenges are different. He indicated that preservation of resources from the former GCRC is a significant issue and further noted that clinical trials are driven by new drugs, approaches, or technologies, some of which are expensive. CTSAs must therefore determine whether they can defray costs of these more expensive technologies through individual institutions or regional facilities. Dr. Orwoll agreed that the GCRC-CTSA transition is a problem and clarified that OHSU has pledged to maintain the level of support for the GCRC until the next round of funding. Dr. Orwoll added that although innovation is important, in light of tight funding OCTRI will need to prioritize its pursuits. For this reason, it has emphasized the formation of partnerships and the use of existing resources in partner institutions.
Dr. Schatten observed that the CTSA at the University of Pittsburgh is doing an admirable job in providing “one-stop shopping” for career mentoring, even as the career trajectory appears to be dismal for physician-scientists and there are so many disincentives for M.D.s to enter research. The Pittsburgh CTSA also has done well in streamlining the IRB approval process, but not as well at the science of science administration. Dr. Orwoll acknowledged the number of people dropping out of research following the end of their K awards. He noted that the national CTSA Consortium understands the regulatory and administrative hurdles facing investigators and how these hurdles impede science, and he expects that the number of top academic health centers focusing on this issue will make a difference.
Dr. Morris pointed out that the training program has been the most successful experience of the CTSA at the Washington University of St. Louis. The University is also trying to involve the community in CTSA-affiliated research. Dr. Orwoll noted that the steepest learning curve for OCTRI was in planning partnerships with Kaiser as investigators from OHSU and Kaiser worked to develop similar perspectives. However, as the CTSA program has grown and its resources or efforts have become more apparent, OCTRI has seen a coalescence of existing and new population- and community-based research.
A. Neuroscience: The Emerging Role of Signal Transduction in Alzheimer’s Disease
Dr. Dale Bredesen, Professor, Director, and CEO of the Buck Institute for Age Research and NACA member, described his research on Alzheimer’s disease (AD). Over 50,000 papers have been published on the amyloid-ß peptide (Aß) that collects in the brains of patients with AD, leading to numerous theories that have two points in common: (1) Aß is thought to be toxic by chemical and physical means, such as metal binding, reactive oxygen species production, and membrane damage, among other effects; (2) the physiological function of this widely-produced peptide is not yet clear. Dr. Bredesen is looking at the signaling pathways that generate Aß and the possible anti-trophic activity of Aß. The trophic factor hypothesis, proposed by 1986 Nobel Prize winner Rita Levi-Montalcini, assumes that withdrawal of a trophic factor is associated with a loss of positive survival signal such as that associated with Akt phosphorylation. However, recent evidence suggests that this loss is only part of the story. Withdrawal of a trophic factor might also result in the specific induction of cell death in neuronal cells mediated by dependence receptors. For example, the dependence receptor DCC, a conditional tumor suppressor that is deleted in colorectal cancer, induces apoptosis when not bound to its ligand. This induction depends on caspase cleavage of DCC. Thus, dependence receptors function as molecular switches. In the presence of trophic ligands, they facilitate classic signal transduction that prevents cell death. In the absence of those ligands, or in the presence of anti-trophins, caspase cleavage of the dependence receptors is enhanced, producing fragments that induce cell death.
Many AD studies have focused on amyloid precursor protein (APP) and Ab, which is produced from cleavage of APP. However, another toxic protein, C31, is produced by caspase cleavage at a different site in APP, and production of C31 is somewhat elevated in patients with AD. To study these peptides, Dr. Bredesen’s group created transgenic mice that could or could not produce the C31 peptide. They found that the C31 cleavage event is critical for synaptic loss to occur. They also observed that a transgenic strain of mice that could produce a lot of Ab but carried a mutation at the C31 caspase cleavage site in APP, which prevented C31 production, behaved similarly to and had just as many synapses as control mice, even though they exhibited as much oxidative damage and as many brain plaques as transgenic AD. Moreover, atrophy seen as early as 2 months in AD mice was not observed to the same extent in mice carrying the mutated C31 cleavage site. Thus, production of C31 may mediate some of the toxic effects of APP cleavage.
Dr. Bredesen’s group has begun to dissect the downstream network of APP-mediated molecular signaling events. Using target-assisted iterative screening (TAIS), a rapid approach to the identification of novel protein-protein interactors, they have identified several candidates, including phosphorylated p21-activated kinase; X11a, which interacts with many putative transcriptional regulators; TAZ, which is involved in stem cell development; and Yap, which regulates cellular size. With further study, Dr. Bredesen’s group could show APP-dependent transactivation of these potential molecular targets. Another candidate target was netrin-1, which they found could serve as a ligand for APP. Organotypic slice cultures from their transgenic mice showed a large amount of Ab, but addition of netrin-1 to the cultures dramatically reduced Ab content. Moreover, hemizygous mice deficient in netrin-1 exhibited more Ab in their brains than control mice did.
These studies suggest a new model for AD, in which APP, like other dependence receptors, serves as a molecular “switch” that is processed in two alternative ways, leading to different signals, depending on its ligand binding. Interaction with Ab could trigger one pathway in which APP is cleaved into four peptides, including Ab and C31, which induce cell death. Because Ab induces further cleavage of APP that produces even more Ab, it could serve as a new type of prion or an anti-trophin. A different APP cleavage event, however, could yield three peptides that are protective and block cell death, and this APP trophic factor pathway might act as an endogenous anti-prion mechanism.
In response to questions from Dr. Schatten, Dr. Bredesen confirmed that apoE and tau, which also have been implicated in AD, are conspicuously absent from his model. However, he pointed out that downstream from APP are several kinases that phosphorylate tau. Thus, the APP signaling pathway he described could ultimately activate phosphorylation of tau. How apoE fits into this pathway is not clear, and whether the pathway itself occurs in human disease is not known.
Dr. Hodes asked about an empirical approach for designing small molecules that could intervene in this APP signaling pathway. Dr. Bredesen responded that his group has set up several assays and that work is underway.
B. Aging Biology: Central Regulation of Bone Mass
Bone remodeling, a physiological process that renews the skeleton throughout life and is disrupted in osteoporosis, serves as a survival function by repairing macro- and microdamage. It occurs simultaneously in several locations and requires a constant energy supply. Gonadal failure appears to favor bone loss, whereas obesity appears to protect from it. Thus, bone remodeling, energy metabolism, and reproduction are likely regulated by the same hormones.
Dr. Gerard Karsenty, Paul Marks Professor and Chair of the Department of Genetics and Development at Columbia University, presented data from studies of leptin, a peptide hormone that regulates appetite and reproduction. Its receptor is located on the hypothalamic neurons and it has a single ligand. Mice that are homozygous for loss-of-function mutations in the leptin gene and thus deficient in leptin signaling show increased bone mass resulting from increased bone formation. This increase in bone mass does not result from the obesity of the animal however; mice that have no adipocytes also show an increase in bone mass in the absence of leptin. Central delivery of leptin corrects the bone phenotype in these mice. Within the leptin receptor complex, a mutation that changes tyrosine 985, which is involved in negative feedback regulation through the SOCS-3 protein, results in normal appetite and energy expenditure but lower bone mass. Thus, the evidence suggests cross-talk between bone and energy metabolism, as well as central control of bone mass. Similar results have been observed in humans. Patients with lipodystrophy exhibit advanced bone age, as do those deficient in leptin.
Leptin deficiency can have adverse consequences on several organs/systems, e.g., behavioral abnormalities, small brain size, defects in wound healing and immunity, and low sympathetic tone. In mouse models, sympathetic tone appears to mediate the effects of leptin on bone mass, and several clinical studies suggest that treatment with beta blockers increases bone mass. Dr. Karsenty and colleagues have thus looked further at the central control of bone mass. Their recent studies have focused on serotonin, because patients with severe depression exhibit low serotonergic tone and bone mass and because selective serotonin reuptake inhibitors (SSRIs) affect bone remodeling. Dr. Karsenty presented preliminary data from these studies.
Dr. Khosla noted that osteoblast function becomes defective with age, resulting in reduced bone formation, and he asked whether any evidence from mouse or human models suggests that sympathetic tone to bone increases with age and perhaps contributes to age-related bone loss. Dr. Karsenty responded that his group has not yet studied this question. Dr. Bredesen also noted the impact of progesterone on setting sympathetic tone and asked whether it affects bone density. Dr. Karsenty responded that his group has measured all sex hormones in their models and found no modifications in the hormonal profile.
C. Geriatrics and Clinical Gerontology: Selective Serotonin Reuptake Inhibitors and Bone Health: Evidence From the Study of Osteoporotic Fractures
Serotonin is a monoamine neurotransmitter with important roles in the central nervous system, gastrointestinal tract, and cardiovascular systems. The concentration of extracellular and synaptic serotonin is regulated by the serotonin transporter system, a plasma membrane transporter that uptakes released serotonin. Functional serotonin receptors and the serotonin transporter have been identified in osteoblasts, osteocytes, and osteoclasts, raising the possibility that inhibition of the serotonin transporter—the primary mechanism of action of SSRIs—could have detrimental effects on bone metabolism. Evidence of an effect of SSRIs on bone health in preclinical animal studies has been mixed, with some studies demonstrating reduced bone mass and altered bone architecture and other work suggesting a possible anabolic effect. Because of the widespread use of SSRIs, understanding their possible effects on bone outcomes is of significant public health importance.
Dr. Susan Diem, Assistant Professor of Internal Medicine at the University of Minnesota, discussed analyses from the Study of Osteoporotic Fracture (SOF), an NIA-funded prospective cohort study of older women. In these analyses and in age-adjusted models, women using SSRIs had a higher average annual rate of bone loss at the hip than did women not using SSRIs. However, the rate of bone loss among users of tricyclic antidepressants (TCAs), an older class of medications, was similar to that observed among nonusers. SSRI results were similar at the femoral neck and trochanter and in multivariable models controlling for potential confounders (age, race, health status, functional status, physical functioning, smoking status, cognitive function, calcium supplement use, vitamin D supplement use, estrogen use, thiazide use, bisphosphonate use, body mass index, weight loss, and depressive symptoms). Depression and depressive symptoms have been associated with lower bone mineral density, and because SSRIs are most commonly prescribed for depressive symptoms, it is possible that this may explain some of these findings. Yet, results were similar when the analyses excluded participants with Geriatric Depression Scale scores indicative of the presence of depression.
Dr. Diem cautioned that data from this observational study cannot be used to establish a causal relationship between SSRI use and higher rates of bone loss. However, she emphasized that, in light of the widespread use of SSRIs, these results suggest a need for further study on the relationships between SSRI use and bone outcomes. Ongoing analyses in the SOF cohort are examining the associations between the use of SSRIs and TCAs and risk for subsequent fractures.
Dr. Kenneth Langa asked whether Dr. Diem and colleagues have looked at adults treated for social anxiety disorder, general anxiety, or social phobia. Dr. Diem responded that SOF did not collect information about indications for SSRI use, although other cohorts might have that information. She was not sure whether looking at such patients would address the problem of confounding by anxiety, but she did note that SSRIs also are used to treat menopausal symptoms and that studies in these patients might yield information about bone metabolism that was not confounded by depression.
In response to questions about partitioning results based on differences in dosage, Dr. Diem clarified that SOF did not collect specific information about dosage. The average length of SSRI use among women in the SOF cohort was not known. In response to questions about clinical characteristics and laboratory values, Dr. Diem noted that blood was drawn from SOF patients and stored but that the researchers do not have information about chemistries at specific study visits.
Dr. Orwoll discussed similar results from the Osteoporotic Fractures in Men Study (MrOS) cohort and noted Dr. Karsenty’s suggestion that central mechanisms tie together energy metabolism, reproduction, and bone metabolism. He asked whether the observed serotonin effects could be sex specific. Dr. Diem responded that MrOS reported cross-sectional data showing lower bone mineral density in SSRI users but that prospective data are still being collected. Dr. Karsenty noted that in his animal studies, males and females exhibited similar phenotypes.
Dr. Orwoll also referred to the comparison between TCAs and SSRIs and noted the appearance of what might be a tricyclic effect with fractures, raising the possibility of some type of neurological effect on falls and other causes of fractures. Dr. Diem responded that the TCA issue is complicated. TCAs have been associated with risk for fracture, most likely because of increased risk for falls resulting from orthostatic hypotension. Although SOF did not show an increased rate of bone loss with TCA, Dr. Diem cautioned that TCAs are now prescribed for sleep disturbance or chronic pain, at lower doses than those used for depression. Dr. Diem also noted the heterogeneity among SSRIs in the degree of serotonin inhibition. It is difficult to know what is happening with TCA use, but the observation of a relationship with fractures but not bone loss suggests a different mechanism than that connected with SSRI use.
Dr. Eisdorfer asked about benzodiazepine use in the SOF cohort as benzodiazepines are associated with an increased risk for falls and are typically coprescribed with SSRIs. Dr. Diem responded that benzodiazepine use is similar between SSRI users and nonusers in the SOF cohort and that an analysis excluding benzodiazepine users yielded similar results.
D. Behavioral and Social Research: Cognitive Impairment and Dementia in the United States: Initial Findings From the HRS and ADAMS
Dr. Langa, Associate Professor, Department of Internal Medicine, University of Michigan, presented findings from a substudy of the Health and Retirement Study (HRS), the Aging, Demographics, and Memory Study (ADAMS), which focused on dementia and cognitive impairment without dementia (CIND). ADAMS is the first nationally representative, population-based study of dementia in the United States to include subjects from all regions of the country. Results suggest that in 2002, the prevalence of dementia among individuals aged 71 and older was 13.9 percent, or approximately 3.4 million individuals. The corresponding values for AD were 9.7 percent and 2.4 million individuals. Dementia prevalence increased with age. An estimated 5.4 million people (22.2 percent of individuals aged 71 and older) had CIND, the most prominent subtypes of which included prodromal AD and cerebrovascular disease. Among ADAMS participants who completed followup assessments, 11.7 percent with CIND progressed to dementia annually, whereas those with subtypes of prodromal AD and stroke progressed at annual rates of 17–20 percent. On the basis of these results, more than one-third of adults aged 71 years or older are affected by dementia or CIND, and the prevalence of these conditions among older adults is of particular public health importance in light of the likely increase in the number of affected individuals as the older population grows significantly in the future.
Dr. Langa also presented results from a study using HRS data to examine population trends in the prevalence of mortality and cognitive impairment consistent with dementia (CI) between 1993 and 2002. This study defined CI using the 35-point HRS cognitive scale and did not include data from ADAMS. Study results showed a higher prevalence of CI among adults aged 70 years or older in 1993 than in 2002. Although CI was associated with a significantly higher risk for 2-year mortality in both years, the risk for individuals with moderate to severe CI was greater in 2002 than in 1993. Education was protective against CI, but among individuals with CI, more education was associated with higher 2-year mortality. These findings suggest a compression of cognitive morbidity between 1993 and 2002, with fewer older Americans reaching a threshold of significant CI and a more rapid decline to death among those who did reach it. Societal investment in building and maintaining cognitive reserve through formal education in childhood and continued cognitive stimulation during work and leisure in adulthood might help limit the burden of dementia among the growing number of older adults worldwide.
Many studies have linked caregiving with increased caregiver morbidity and mortality. However, these studies do not disentangle the effects of providing care from those of continuous exposure to an ailing loved one with serious health problems. Dr. Langa reported results from a new study led by Dr. Stephanie Brown that used data from the HRS to examine the relationship between mortality and the provision of informal care to a disabled spouse. After controlling for functional and cognitive limitations of the spouse, and for demographic and health characteristics of the caregiver, this study found that the number of hours spent providing care to a spouse (i.e., 14 hours per week or more) predicted decreased mortality for the caregiver. These findings suggest that it might be premature to conclude that health risks for caregivers arise from the active provision of care. Indeed, under some circumstances, caregivers may derive health benefits from providing care.
In response to questions from Ms. Reid, Dr. Langa noted that lower net worth of the families was associated with higher mortality risk among caregivers. He also pointed out, however, that when socioeconomic status was separated out, caregiving was still associated with lower mortality risk.
Dr. Hodes asked about the capacity of HRS and ADAMS to monitor trends over time. Dr. Langa acknowledged that although ADAMS assessments over time are ideal, they are expensive. How best to integrate such an expensive study into HRS is not yet clear, nor is it clear whether predictions can be done without ADAMS assessments.
Dr. Brummel-Smith asked about distinctions of vascular causes from stroke in CIND, notification of participants about their ApoE status, and outcomes for those receiving that information. Dr. Langa responded that the study team did not report ApoE4 status or research diagnoses to study participants but did send letters with this information to participants’ primary physicians. Although the study team has some anecdotal information, no formal study of outcomes has been done. Dr. Suzman added that a study led by Dr. David Weir informed participants’ physicians if the participants had high glycosylated hemoglobin readings and that a modest effect on outcomes has been observed for those participants whose physicians were informed. With respect to distinguishing vascular causes from stroke, a participant was said to have vascular mild cognitive impairment if he or she had documented cardiovascular risk factors but had not had a stroke.
Dr. Orwoll commented that one of the tables shown by Dr. Langa suggested that although the prevalence of dementia was higher among women, it looked like the prevalence of early dementia was higher and the rates caught up at later ages in men. Dr. Langa responded that because of confidence intervals with respect to sample size, he was wary of making sweeping conclusions about gender. However, he did acknowledge that, at this point, Dr. Orwoll might be right.
Dr. Orwoll also referred to the finding that dementia rates were falling and asked whether they were truly falling or whether the onset of disease was merely delayed. Dr. Langa responded that the age structure of the 1993 and 2002 cohorts were similar but that CI did appear to push toward the end of life, supporting a hypothesis of compression of cognitive morbidity. Among the individuals aged 71 years or older, the number of those with significant CI or dementia was lower. Thus, it appears that onset occurred later and that individuals died more quickly once disease onset had occurred.
In response to questions about history of delirium or anesthesia, Dr. Langa reported that his study team is completing a manuscript on anesthesia and effects on CIND and dementia using Medicare billing data.
Dr. Ganguli noted that some questions could be answered with incidence data, and she asked how much followup data HRS and ADAMS have. Dr. Langa responded that his team would not be able to do a classic incidence study with the gold standard set by ADAMS but that he hoped HRS data could be used to make a reasonable attempt at this information.
Dr. Bredesen asked whether ADAMS was revealing information about one disease or whether adults could begin with any abnormality and eventually reach a stage of dementia. Dr. Langa responded that because the criteria for dementia and CIND set up a circular argument, answering that question is difficult. However, he did notice different patterns based on when different cognitive difficulties arose and that these differences might be related to various causes.
The open session of the 105th meeting of the National Advisory Council on Aging was adjourned at 2 p.m. on September 25, 2008. The next meeting is scheduled for January 27 and 28, 2009.
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 Robin Barr, D.Phil.
With assistance by Rose Li and Associates, Inc.
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. (Back to text.)
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. (Back to text.)
- These minutes will be approved formally by the Council at the next meeting on January 27–28, 2009, and corrections or notations will be stated in the minutes of that meeting. (Back to text.)
NATIONAL ADVISORY COUNCIL ON AGING
NATIONAL INSTITUTE ON AGING
(Terms end December 31) (*WGoP Member)
Richard J. Hodes, M.D.
Director, National Institute on Aging
National Institutes of Health
Dale E. Bredesen, M.D. (2011)
Professor, Director & CEO
Buck Institute for Age Research
8001 Redwood Boulevard
Kenneth V. Brummel-Smith, M.D. (2009)
Professor and Chair
Department of Geriatrics
Florida State University College of Medicine
Peggye Dilworth-Anderson, Ph.D. (2010)
Professor, Health Policy & Administration
Associate Director, Aging and Diversity/ Institute on Aging
University of North Carolina, Chapel Hill
Chapel Hill, NC
Carl Eisdorfer, Ph.D., M.D. (2009)
Knight Professor and Director
Center on Aging
University of Miami
Lawrence M. Friedman, M.D. (2009)
*Mary Ganguli, M.D., M.P.H. (2009)
Professor of Psychiatry, Neurology, and Epidemiology
Department of Psychiatry
University of Pittsburgh
Paul Greengard, Ph.D. (2008)
Vincent Astor Professor
Laboratory of Molecular & Cellular Neuroscience
The Rockefeller University
New York, NY
*S. Michal Jazwinski, Ph.D., (2010)
Department of Medicine
Tulane University Health Sciences Center
New Orleans, LA
Sundeep Khosla, M.D. (2010)
Professor, Endocrine Research Unit
Division of Endocrinology, Metabolism, & Nutrition
Mayo Clinic College of Medicine
Mills, Terry L., Ph.D. (2008)
Dean, Division of Humanities & Social Sciences
*John C. Morris, M.D. (2009)
Washington University School of Medicine
St. Louis, MO
Orien Reid (2010)
Chairman, Alzheimer's Disease International
President, Consumer Connection
*Gerald P. Schatten, Ph.D. (2009)
Professor, Pittsburgh Development Center
Magee-Womens Research Institute
University of Pittsburgh
Albert L. Siu, M.D., M.S.P.H. (2008)
Ellen and Howard C. Katz Professor
Chairman, Brookdale Department of Geriatrics and Adult Development
Mount Sinai School of Medicine
The Mount Sinai Medical Center
(and Director, Geriatric Research, Education, and Clinical Center, Bronx Veterans Administration)
New York, NY
Susan L. Swain, Ph.D. (2011)
President and Director
Saranac Lake, NY
*Mary E. Tinetti, M.D. (2008)
Gladys Phillips Crofoot Professor
Department of Internal Medicine, Epidemiology, and Public Health
Director, Program on Aging
Yale University School of Medicine
New Haven, CT
EX OFFICIO MEMBERS
Michael O. Leavitt
Department of Health and Human Services
Hubert H. Humphrey Building
Elias Zerhouni, M.D.
National Institutes of Health
Public Health Service
James F. Burris, M.D.
Geriatrics & Extended Care Strategic Healthcare Group
Department of Veterans Affairs
Kenneth G. Pugh, M.D.
Commander, MC, U.S. Navy
Department of Medicine
National Naval Medical Center
Director, Center for Planning & Policy Development
U.S. Administration on Aging, DHHS