Council Minutes - January 2011
The 112th Meeting
January 25–26, 2011
- REVIEW OF APPLICATIONS
- CALL TO ORDER
- REPORT: Task Force on Minority Aging Research
- REPORT: Working Group on Program
- PRESENTATION: NAS Report on Divergent Trends in Longevity
- SYMPOSIUM: Progress in Neuroscience of Aging
- INTRAMURAL RESEARCH PROGRAM REPORTS
- REVIEW OF INTRAMURAL RESEARCH PROGRAM
Attachment A: Roster of the National Advisory Council on Aging
Attachment B: Director's Status Report to Council
The 112th meeting of the National Advisory Council on Aging (NACA) was convened on Tuesday, January 25, 2011, at 3 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, January 25, from 3 p.m. to 5 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 the Public Law 92–463.1 The meeting was open to the public on Wednesday, January 26, from 8 a.m. to 1:33 p.m.
Dr. Robert Califf
Dr. Dale Bredesen
Dr. Peggye Dilworth-Anderson (by phone)
Dr. Hugh C. Hendrie
Dr. S. Michal Jazwinski
Dr. Sundeep Khosla (by phone)
Dr. Victor Molinari
Dr. Lennart Mucke
Mr. Daniel P. Perry
Dr. Ronald C. Petersen
Dr. Arlan G. Richardson
Ms. June Simmons
Dr. James P. Smith
Dr. Susan L. Swain
Dr. Terrie F. Wetle (Tuesday only)
Dr. Lisa Berkman
Dr. Andrea LaCroix
Ms. Orien Reid
Ex Officio Participants:
Dr. James F. Burris, Department of Veterans Affairs
Dr. Jane Tilly, Administration on Aging
Absent Ex Officio Participants:
Mr. Robert Hornyak, Administration on Aging
Dr. Kenneth G. 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. Fungai Chanetsa, Center for Scientific Review
Dr. Heidi Friedman, Center for Scientific Review
Dr. Michelle Washko, Administration on Aging
Members of the Public Present:
Mr. Shane Austin, Alzheimer’s Foundation of America
Dr. Barney Cohen, National Academies Committee on Population
Dr. Llewellyn Cornelius, Society for Social Work and Research
Dr. Eileen Crimmins, University of Southern California
Dr. Rose M. Li, Rose Li and Associates, Inc.
Dr. Frances McFarland Horne, Rose Li and Associates, Inc.
Dr. John Morrison, Mount Sinai School of Medicine
Dr. Marcelle Morrison-Bogorad
Dr. Dan Newlon, American Economic Association
Ms. Beth Roy, Social & Scientific Systems
Dr. Sherry Willis, University of Washington
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 552(b)(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 908 applications requesting $1,487,631,626 for all years underwent initial review. The Council recommended 546 awards for a total of $1,048,109,779 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 112th NACA meeting and called the meeting to order at 8:05 a.m. on Wednesday, January 26, 2011.
Director’s Status Report
Dr. Hodes reviewed the budget scenarios he had described at the September 2010 Council meeting. In one scenario, the FY2011 budget would be increased by a sub-inflationary 3 percent in current dollars, representing a slight dip in constant dollars. However, a more likely scenario involves a continuing resolution that remains flat at 2010 levels, which would mean a 3 percent decrease in buying power and a total effective decrease of 17 percent over the past 8 years. It is not clear whether this funding level will hold in light of the new political climate, and no more information is expected until March, when the current continuing resolution expires. In the interim NIA has announced a payline of 9 percentile for all applications under $500,000 (direct costs) in all years, and 6 percentile for applications over $500,000 direct costs in one or more years.
Dr. Hodes then provided an update on the Scientific Management Review Board (SMRB), which was established as part of the NIH Reform Act of 2006 and comprises several Institute and Center (IC) Directors and eminent individuals from outside NIH. This Board advises the NIH Director and provides reports to Congress regarding the use of certain organizational authorities. The SMRB includes four working groups. The Deliberating Organizational Change and Effectiveness (DOCE) working group determines the principles that should be used in organizing NIH. A report has been developed, and working group activities are ongoing. The NIH Intramural Research Program (IRP) working group examines potential sources of stable funding for the NIH Clinical Center. The IRP working group has been deliberating on whether the Clinical Center can become a greater resource for the broader clinical research community, rather than a resource for the intramural community alone.
The Substance Use, Abuse, and Addiction working group (SUAA) considers changes in the NIH structure that might optimize research into substance use, abuse, and addiction. SUAA has recommended establishing a new Institute that would combine the existing SUAA portfolios of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the National Institute on Drug Abuse (NIDA), pull relevant SUAA portfolios from other ICs (for example, NCI tobacco addiction research), and transfer non-SUAA portfolios from these Institutes to appropriate ICs. Because this recommendation also calls for the dissolution of NIAAA and NIDA, it would involve substantial shifts at NIH.
The Translational Medicine and Therapeutics (TMAT) working group identifies ways in which structural or functional changes would lead to more efficient and effective translation of medicine from the basic research through preclinical and clinical phases. TMAT has recommended establishing a National Center for Advancing Translational Sciences (NCATS) to develop and provide research infrastructure, foster innovative strategies, and serve as a catalyst for collaborations in translational medicine. This recommendation has been endorsed by the overall SMRB.
Dr. Hodes further noted that NCATS would be assembled primarily from existing programs in the National Center for Research Resources (NCRR), National Human Genome Research Institute, and the NIH Common Fund. The Clinical and Translational Science Award program would be moved from NCRR to NCATS; other NCRR programs would be moved to other ICs, particularly the National Institute of General Medical Sciences; and NCRR would be dissolved. NCATS also would include the Cures Acceleration Network, which has been authorized by Congress but has not yet received an appropriation. The final budget for NCATS is not yet known, but there are no plans to cannibalize budgets and programs from other ICs for NCATS. Dr. Hodes noted that NIH remains committed to the support of basic, translational, and clinical research and that NCATS is intended to bring existing efforts together in a way that enhances the translational efforts of all ICs, which are pursuing novel and imaginative plans of their own.
Dr. Hodes closed his presentation by noting changes in Congressional committee membership.
In response to questions from Council members, Dr. Hodes clarified that at present, there are no plans for programs to be moved from NIA to NCATS. He also pointed out that many people have been called to advise on the scope of NCATS and that both the academic and industrial research communities have emphasized that NIH should not develop drugs. Rather, most researchers envision NIH developing leads that are taken up by the pharmaceutical industry for further development. Therapeutics for rare and orphan diseases might form one exception, but even in that case, the research community is considering ways to incentivize the pharmaceutical industry to become more involved.
Dr. Califf expressed frustration, on the part of Clinical and Translational Science Award sites (CTSAs), regarding difficulties in organizing the CTSA consortium and developing infrastructure that NIH can use. He called for a better integrated national infrastructure for populations. Dr. Hodes acknowledged that although the CTSAs have accomplished much, the integration and coordination of sites has been slow.
In response to questions about the long-range trajectory of funding, Dr. Hodes noted widespread opinion that a flat budget for the foreseeable future is somewhat optimistic. He noted the need to convince policymakers that despite an immediate need for economy, investment in NIH presents an opportunity to reduce overall health costs and human suffering.
The Council also discussed drug effectiveness research efforts, for example an Agency for Healthcare Research and Quality (AHRQ) initiative to develop a system for studying interventions in primary care practices throughout the nation. Dr. Hodes noted NIH’s involvement in comparative effectiveness research (CER), which received a $1.1 billion boost from the American Recovery and Reinvestment Act (ARRA), and he stated that ARRA-supported efforts have emphasized methodology. NIH, AHRQ, the Centers for Medicare and Medicaid Services (CMS), and the U.S. Food and Drug Administration (FDA) have received an allocation to establish a database and methodology, and NIH is pursuing collaborations with health maintenance organizations to establish a network. NIH is also involved in the newly established Patient-Centered Outcomes Research Institute, which is funded by a tax on health insurance and expected to give emphasis, but not exclusivity, to AHRQ and NIH.
Discussion closed with Dr. Hodes pointing out the increase in press coverage of NIA research, with an estimated 9.4 billion potential readers during 2010 compared to about 3 billion during 2009.
Dr. Hodes recognized Dr. Marcelle Morrison-Bogorad, recently retired Director of the NIA Division of Neuroscience, and welcomed Ms. Fareen Akbar, Program Analyst in the Division of Behavioral and Social Research (DBSR), and Dr. Samir Sauma, new Deputy Director of the Office of Planning, Analysis, and Evaluation, to NIA.
Mr. Robert Hornyak, who is replacing Mr. John Wren as Administration on Aging member, and Dr. Dan Newlon, who retired from the National Science Foundation and is now working with the American Economic Association, also were introduced.
Future Meeting Dates
May 24–25, 2011 (Tuesday and Wednesday)
September 20–21, 2011 (Tuesday and Wednesday)
January 24–25, 2012 (Tuesday and Wednesday)
May 22–23, 2012 (Tuesday and Wednesday)
September 18–19, 2012 (Tuesday and Wednesday)
Consideration of Minutes of the Last Meeting
The minutes of the September 2010 meeting were considered. A motion was made, seconded, and passed unanimously to approve the minutes.
Dr. J. Taylor Harden (Assistant to the Director for Special Populations, NIA) reported that the Task Force had discussed the FY2010 report on the inclusion of women and minorities in NIH research. This report is mandated by the NIH Revitalization Act of 1993. Dr. Harden reported that between 2009 and 2010, enrollment in NIA-supported protocols increased from 163,000 to 523,000 and that enrollment increased significantly for 429 protocols. However, she also noted the number of studies with enrollments of more than 10,000 participants, including a study supported by ARRA funds, and she speculated that with the end of ARRA funding, the next report will show a significant change. NIA has done well consistently in including women in its studies; in 2010, almost 57 percent of research participants were women. NIA also has seen an increase in the percentage of participants that report more than one race, from 0.5 percent in 2003 to almost 3 percent in 2010.
Dr. Harden reported some limitations of the methods used for data collection. They track data provided by investigators in their initial submissions, but they do not track data on changes in recruitment and retention over time. Those data are tracked internally by NIH. In response to questions from Council members, Dr. Harden discussed plans to obtain longitudinal information to determine whether and why the proportion of minority participants in NIA studies has been increasing. NIA expects to present that information at the next Task Force meeting.
The rest of the Task Force meeting was devoted to discussion of the research scientist pipeline and an initiative called Science Left Behind: Broadening Participation in America’s Science, Technology, Engineering, Mathematics, and Medicine (STEMM) Workforce. Increasing the participation of minorities in the STEMM workforce has long been discussed, particularly in light of a 2007 report by the Institute of Medicine that noted a significant drop in interest, both among underrepresented minorities (URM) and non-URM, from undergraduate through graduate and post-graduate participation. Science Left Behind has two priorities: 1) undergraduate retention and completion, and 2) teacher preparation.
Several research opportunities are available at the undergraduate, predoctoral, postdoctoral, and junior investigator levels, but, as Dr. Harden reminded Council members, the undergraduate level might be too late to capture interested individuals. More work is needed to provide research opportunities at the high school level. Yet the Task Force also noted the challenges in engaging undergraduate students in research, and it considered approaches, such as summer programs, mentoring, and research initiatives, that might be appropriate at that level. Dr. Harden closed by mentioning the weeklong NIA Summer Institute, which will be held July 9 through 15 on Maryland’s Eastern Shore. Applications are due on the first Friday in March.
Dr. Victor Molinari emphasized the mentoring aspect, noting his own experiences in which students responded well to their mentoring relationships at summer institutes held at the University of South Florida. He added that for many students, it is not clear what a science research career involves, how to apply to doctoral programs in science, or what opportunities are available. Dr. Lennart Mucke suggested establishing a national resource that students could access for advice, and he expressed support for engaging high school students. He also noted the excitement many students felt at being in the research environment. Dr. Harden invited Council members to contact her with other ideas.
A motion was made and seconded to approve the 2010 report on inclusion of women and minorities in research. The motion was passed unanimously.
Dr. S. Michal Jazwinski reported on two concept clearances. The first is a funding opportunity announcement (FOA) to continue the Health and Retirement Study (HRS), a nationally representative study of Americans aged 50 years and older. The HRS has been ongoing since 1990, and it is in its tenth wave, which will end on December 31, 2011. New NIH policy requires an FOA to be in place so that the HRS may be continued. The Working Group unanimously recommended this concept for approval. The motion was passed unanimously by Council.
The second concept involves a genetic data warehouse for the Alzheimer’s disease (AD) genetic research community. This database was established in 2005 and receives contributions from all AD Centers and the National AD Coordinating Center. All NIA-supported researchers contribute their genetic findings in accordance with NIA policy and award terms. This database has facilitated a U01-supported genome-wide association study, which in turn has led to the discovery and confirmation of three new genes associated with AD. The database has more than 126,000 terabytes of data, but it needs to be upgraded to facilitate primary and secondary analyses and to link to other genomic browsers and databases. The Working Group recommended that the upgrade be approved. The motion was passed unanimously by Council.
Statement of Understanding
Every January, the Council reviews a Statement of Understanding, which describes procedures used when a Council member’s action comes up for review in closed session, outlines a policy for expedited review, and allows for small administrative supplements to keep research going in case of an emergency.
The Council requested no changes to the Statement of Understanding. A motion to approve the Statement was forwarded, seconded, and passed unanimously.
Funding Policy and Practice at NIA
During the previous afternoon’s meeting of the Working Group, Dr. Hodes provided background on the work subcommittees are undertaking to advise NIA leadership in the review and management of grants. He provided an institutional perspective on funding decisions and reviewed some of the actions taken by NIA in light of current strains in budget. NIA hopes that subcommittees will use this information as they develop suggestions by May 2011.
In 2006, the United States had the lowest average life expectancy at age 50, among nations of similar wealth. In addition relative to these nations the United States showed higher rates of heart disease and diabetes and the worst indicators of physiological status. These data spurred the NIA to request that the National Research Council, part of the National Academies, convene a panel of prominent researchers in several disciplines to examine trends in life expectancy at older ages among wealthier countries, understand how and why these trends differ, and provide some information on ways to change the United States’ position relative to other countries. The panel limited its examination to ages older than 50 years, because the life expectancies from birth are similar across countries and because the causes of death at ages younger than 50 differ from those at ages older than 50. The panel also limited its examination to 10 countries that could provide a reasonable amount of data, and it examined trends among men and women separately. The panel then examined major hypotheses explaining divergent trends. The panel has produced a volume that includes 14 background papers, as well as an overarching report released on January 25, 2011. Panel co-chair Dr. Eileen Crimmins (University of Southern California) summarized this report for the Council.
Japan, France, Italy, and Spain show the highest life expectancy at age 50, whereas the United States, the Netherlands, and Denmark all show the lowest. The lag among men is significantly lower than that seen for women in the United States. In 1950 American women showed similar life expectancy as women in other countries, but over time, life expectancy among women in the United States, Denmark, Great Britain, and the Netherlands has declined, whereas that among women in Japan, France, and Australia has increased. The panel also found that life expectancy has decreased most significantly among younger women from 1950 through 2006. Thus clear differences are apparent by both age and sex.
Trends in heart disease account for most of the differences in life expectancy between the United States and other wealthy nations. Trends in deaths due to circulatory diseases (stroke), respiratory diseases, lung cancer, and diabetes also play a large role in these differences. Data on indicators of health were more difficult to obtain, but on the basis of a large set of international studies comparable to the HRS, the panel also found more disability and loss of function in the United States, compared with other wealthy nations. The United States does excel, however, in cancer screening and thus shows higher life expectancy among patients with cancer. Denmark and the Netherlands differ in causes underlying their lower expectancy. Denmark shows a higher prevalence of stroke, whereas the Netherlands shows a higher level of respiratory diseases. Japan, on the other hand, is exceptional in life expectancy and all causes of mortality, except for stroke.
Smoking accounts for a large amount of differences in life expectancy. In the United States, the elimination of smoking could increase life expectancy by 2.3 years among women, and by 2.5 years among men. Although the prevalence of smoking has generally declined in the United States, smoking is a 30-year-old problem, and many individuals aged 50 and older have a history of smoking. In 1955, 1980, and 2003, approximately 23 percent of deaths in women in the United States were attributable to past or current smoking. In France, Italy, and Spain, on the other hand, there has been almost no mortality from smoking among older women, because they did not smoke when they were younger.
Obesity also might be a reasonable candidate in explaining differences in life expectancy, because the United States leads the 10 countries in level of obesity. Current research indicates a change over time in mortality among obese individuals, compared with that among individuals of normal weight, but the estimated effect of obesity on mortality also appears to have fallen over time. The concomitance and progression of obesity to other health problems has been reduced by treatment of high cholesterol, hypertension, and diabetes. In addition, as with smoking, a history of obesity, not just an individual’s current state, also appears to play a role in mortality. Data indicate a gain in life expectancy, for both men and women, if obesity were eliminated, but the extent of the effect of obesity on mortality remains difficult to determine.
Other factors either contributed little to the effect (lack of health insurance, low SES, social interaction and integration, hormone therapy) or could not be estimated because of insufficient data (physical activity, stress).
Dr. Crimmins noted that the effect of reduced smoking will continue to improve mortality among men in the United States, but that the smoking history of women will continue to slow progress in U.S. life expectancy over the next couple of decades. The effects of obesity, particularly the number of individuals who are obese and how long they might be obese, are not yet clear. Dr. Crimmins indicated that the report is only a beginning and that the panel has not considered factors such as genetics, early life, psychosocial factors, stress, culture, and the natural environment.
Dr. Hugh Hendrie observed that the effects of obesity on mortality might depend upon when one starts measuring them. He and his colleagues have suggested that for individuals older than 65 years, declines in weight might have adverse effects on health. He also expressed some concern about measurements of relative income inequality, particularly when one considers out-of-pocket health care costs. Dr. Crimmins responded that the effects the panel had observed depended in part on a lifetime of obesity. She also acknowledged Dr. Hendrie’s point about relative income inequality and suggested that more study is needed.
In response to observations that life expectancy has increased in all the countries except for Denmark, Dr. Crimmins noted that the prevalence of smoking and drinking is higher in Denmark than in other countries and that Denmark has spent less on health care. However, Denmark has improved in recent years. Dr. Crimmins also noted that the Netherlands appeared to be efficient in all aspects of health care but has not provided all those aspects to older people because of budgetary constraints.
Other Council members remarked that divergence in life expectancy trends between the United States and other countries is not simply an issue of access to health care, but also of health status and behaviors. Questions were raised about overtreatment of risk factors, compared with encouragement of lifestyle changes, and how to convey a sense of urgency if life expectancy in the United States is 81 years, compared with 83 years in other countries.
This symposium was held in honor of Dr. Marcelle Morrison-Bogorad, recently retired Director of the Division of Neuroscience.
Synaptic Correlates of Cognitive Performance: Implications for Cognitive Aging
In AD, cortical connections are compromised as vulnerable neurons die and circuits deteriorate. Although AD is a human disease, non-human primates are vulnerable to age-related cognitive decline, which may involve many of the same circuits affected by AD but manifests vulnerability at the synapses rather than in the neurons. As hypothesized by Miller, the primate dorsolateral prefrontal cortex (dlPFC) encodes the rules for goal-directed behavior and processes changes in those rules. It is likely that these processes require extensive neuronal and synaptic plasticity. Neurons that are involved in processes requiring the dlPFC and lost in AD each have 10,000 to 20,000 spines, receive excitatory synapses, and contain proteins linked to plasticity, learning, and memory. Dr. John Morrison, of the Mount Sinai School of Medicine, is studying monkeys to learn more about the cellular and synaptic changes involved in age-related cognitive decline.
Aging monkeys take longer to perform delayed response and delayed non-matching to sample (DNMS) tasks, reflecting declines in the prefrontal cortex, and their memory performance worsens as delay lengthens. Neuronal spines do not appear to degenerate with age in the monkey, but Dr. Morrison and colleagues have found age-related decreases in spine density, which have been linked with plasticity and learning. This loss primarily affects thin spines, which are unstable, motile, weakly activated, and dominated by proteins involved in plasticity and learning. Large spines, which have large 2-amino-3-(5-methyl-3-oxo-1,2- oxazol-4-yl)propanoic acid (AMPA)-mediated currents and contribute to strong, stable synaptic currents, remain unaffected by age. Total axospinous synapse density correlates with the ability to learn the DNMS task, but the density of the smallest spines is more predictive of learning ability. Thus age-related cognitive decline is likely associated with the loss of spine-synapse formation, turnover, and plasticity.
The circuits that are affected by age-associated cognitive decline and AD also are affected by steroids such as estrogen. In delayed-response experiments with ovariectomized monkeys, Dr. Morrison and colleagues have found that aged monkeys perform just as well as younger monkeys in the absence of estradiol. However, younger animals have three times as many small thin spines as aged animals do, and aged animals who are given exogenous estradiol exhibit a partial restoration of these spines. These results suggest that age-associated cognitive decline might be partially reversible.
The work by Dr. Morrison and colleagues thus suggests that the outgrowth of small, motile, transient spines is a key element in the plasticity required for learning and changing rules for goal-directed behavior. Age-related cognitive decline is linked both to loss of these spines and loss of estrogen-enhanced cognition. However, the estradiol effect observed by Dr. Morrison suggests that spine loss is not inevitable and thus presents a candidate for behavioral or pharmaceutical interventions designed to protect against cognitive decline. In addition, if synapse loss leaves humans vulnerable to neuronal death, the loss of thin spines might present a target for intervention before neuronal death occurs.
The bulk of discussion focused on technical aspects of Dr. Morrison’s work. However, Dr. Morrison did note that most mouse models of AD show synapse and spine loss and that in vitro studies suggest that circulating amyloid is toxic to synapses. Humans with AD lose a large number of synapses, but the class of spines lost has not been defined. Council members also discussed human studies showing that estrogen intervention has no effect against AD, as well as studies suggesting that the timing of ovariectomy and hormone therapy affects onset of AD.
International Studies in Comparative Epidemiology on Dementia Risk
Dr. Hendrie presented results from three community-based comparative studies. The first has focused on dementia screening methods in Indian and non-Indian populations in Manitoba. A preliminary pilot study compared elderly Cree living in two reserves with non-Indian Winnipeg residents and found a low prevalence of AD among the Cree. Survey respondents indicated that the Cree advantage might be related to diet, which contains a large amount of fish; social engagement, because elderly Indians hold respected roles in society; and the use of traditional medicines. Overall dementia risk was similar, however, because of a large incidence of dementias related to alcohol use.
In a second study, Dr. Hendrie and a collaborator from Nigeria compared elderly Yoruba in Nigeria with African Americans in Indianapolis. They found that the incidence of AD is twice as high in African Americans as it is among the Yoruba. They also found that apoE4 genotype is not a risk factor in Yoruba as it is in African Americans, even though the interaction between apoE4 and cholesterol is similar in the two populations. It is likely that the differences arise from gene-environment interactions, particularly exposure to environmental factors that exert epigenetic modifications.
Selenium is a component of the antioxidant enzyme GP-X, and low selenium levels have been associated with major chronic diseases. However, data regarding an association between selenium levels and cognitive decline are inconsistent. Because the brain has a ready supply of selenium, long-term exposure to this element might be necessary to assess an effect. However, availability of a long-term food source is also necessary, as selenium content in food is highly variable depending on soil content. Thus, in the third study, Dr. Hendrie and colleagues assessed selenium levels in rural elderly Chinese, who eat locally grown food, in areas where soil content has been monitored regularly. They found a linear relationship between selenium content and cognitive scores. Although they also have found a correlation between high blood pressure, particularly high systolic blood pressure, and cognitive decline, the effect of blood pressure on cognition might be mitigated in part by traditional medicines, even if these medicines have no effect on blood pressure itself.
Serial MRI and CSF Biomarkers in Normal Aging, Mild Cognitive Impairment, and Alzheimer’s Disease
A theoretical model of AD progression comprises a pre-symptomatic phase, early mild cognitive impairment (MCI), late MCI, and full dementia. Each phase in the model has a specific set of clinical characteristics and biomarkers; for example amyloid deposits can be measured during the pre-symptomatic stage, and neuronal death can be observed during early or late MCI. Dr. Ronald Petersen and colleagues examined two datasets—one from the AD Neuroimaging Initiative (ADNI) and one from the Mayo Clinic Study of Aging—to further validate this model. ADNI is a simulation of clinical trials in which 200 normal participants, 400 participants with MCI, and 200 participants with AD undergo magnetic resonance imaging (MRI), fluorodeoxyglucose positron emission tomography (FDG-PET), cerebrospinal fluid analysis (CSF), and amyloid imaging. The Mayo Clinic Study of Aging is a population-based study of almost 3,000 individuals aged 70 to 89 years in Olmsted County, Minnesota. About 75 percent of the sample is normal, 14 percent have MCI, and 11 percent have dementia. Clinical and performance measures, quantitative MRI scans, DNA samples, and frozen plasma and serum samples are available for these participants, who undergo follow-up approximately every 15 months.
On the basis of these data and on clinical MCI criteria established in 1999 and revised in 2004, Dr. Petersen graphed clinical phenotypes with the presumed etiologies of underlying syndromes, and derived possible outcomes. AD most often progresses from the amnestic form of MCI, although there are atypical forms. The biomarker data not only suggest clinical utility, but also a way to stratify future clinical study populations for more efficient trial design. Neuroimaging data confirmed volumetric changes in the medial temporal lobe, amyloid, and temporoparietal patterns as markers of progression through the theoretical spectrum. Most of these characteristics mesh with the idea of amnestic MCI as the prodromal stage of AD. However, in the community sample, Dr. Petersen and colleagues have seen positive amyloid imaging in 30 percent of normal participants, 60 percent of participants with MCI, and almost all participants with AD. It is not clear whether the normal participants with positive amyloid scans are in the preclinical stages of impairment. It is possible that MCI represents a heterogeneous condition; longitudinal data are needed to tease this out.
Several efforts are under way to revise the diagnostic criteria for MCI, including those by the American Academy of Neurology, NIA, the Alzheimer’s Association, and those developing the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Each effort aims to further define the pre-clinical stage of AD. However, MCI alone as a clinical syndrome is neutral with respect to AD. The ability to determine whether MCI is due to AD will depend on the level of confidence in molecular and neuronal biomarker test results. Efforts are now under way to review evidence-based medicine for both MCI and dementia, in light of new data. The ultimate goal is to streamline clinical trials, increase confidence in diagnosis, and develop therapeutics to intervene as soon as possible in AD-related MCI.
Dr. Molinari asked about the ethics of earlier detection of cognitive impairment, particularly given the lack of treatments for AD. Dr. Petersen responded that the work still should be done so that clinicians have the information to move forward when therapeutics become available. He emphasized the importance of educating individuals about their risk in an objective manner, but also expressed concerns about the ability of at-risk individuals to obtain insurance if such information is present in the medical record. Dr. Dale Bredesen advocated detecting and diagnosing AD at earlier stages, when there is still a chance to prevent it. Other Council members noted that earlier detection also is necessary for further research. Dr. Petersen recognized the need for a peripheral, cheap, noninvasive biomarker that can be used to stratify the population. Those at most risk would then be candidates for the more expensive testing.
Healthy Cognitive Aging: Findings from the Seattle Longitudinal Study
Dr. Sherry Willis, of the University of Washington, presented results from the Seattle Longitudinal Study (SLS). The study has information on individuals from young adulthood to old age, but she focused her presentation on midlife, defined as 40 to 60 years. Dr. Willis noted that the Seattle Longitudinal Study was initially designed as a study of normal aging, not a prospective study of dementia.
Decline in episodic memory can begin as early as midlife and becomes steeper by age 60. Some individuals show gains in episodic memory and remarkable plasticity at midlife. Among adults aged 70 to 80 years, those who are classified as possibly or probably having AD showed a steeper rate of loss in episodic memory at midlife. The study sample shows considerable variability at midlife, and patterns that begin at midlife persist through old age.
The study team also studied influences on cognitive aging and has begun neuroimaging and biomarker studies. For some individuals imaging data are available only at old age, but cognitive data at midlife. However, correlations have been observed between imaging changes and midlife changes in episodic memory. Hippocampal volume is smaller among individuals who experience declines, compared with that seen among those who gain function, and “gainers” and “decliners” show differences in white matter integrity. Midlife changes in executive function, episodic memory, and psychomotor speed have been examined further and modeling performed to determine predictors of the level of function and rate of change from midlife to old age. Several midlife predictors have been identified. For example, apoE is the most salient predictor of the rate of change in episodic memory. Set shifting, a component of executive function that allows individuals to be flexible and show sets across problem solving, is another predictor of the level of function and rate of change in midlife. Gender, education, and lifestyle factors also affect the level of function in midlife. “Gainers” are less likely to have been diagnosed with hypertension at midlife, and even among well-educated individuals, more work routinization is seen among those who show a decline in midlife.
Dr. Willis and colleagues have also examined generational differences in fluid abilities, these which encompass reasoning, psychomotor speed, and episodic memory and begin to decline at age 60, and crystallized abilities, which include vocabulary and verbal meaning, which start to decline in the 70s. They have found the rate of change is steeper in the earlier-born cohorts.
One component of Dr. Willis research is a trial examining the effects on plasticity of an intervention, involving training in executive reasoning or spatial ability among individuals with no symptoms of MCI or dementia. On average, those who were trained showed more plasticity than those who were not, even into their 80s. Trained individuals showed some decline in ability during the 7 years between boosters, but not to pre-training levels. Thus, even though plasticity declines with chronological age, consistent training and boosting can aid in maintaining a level of function. Further examination suggests that differences in the level of function before intervention can predict who might be at risk to be later classified as possibly or probably having dementia.
A small part of the SLS also has examined social context by following 180 married couples for at least 20 years. Within these couples, individuals became more similar in life satisfaction and cognitive function as they aged together. For example, with cognitive ability, the less able spouse begins to resemble the more able spouse. Thus cognitive function is dynamic and relational.
Questions from the Council focused on technical aspects of the study.
Comments from Dr. Marcelle Morrison-Bogorad
Dr. Morrison-Bogorad saw this symposium as a timely update on ground-breaking science both in normal aging and in AD. She considered the symposium to be a wonderful opportunity for her to reflect upon her time at NIA and to see the progress during her tenure as Director of the Division of Neuroscience. She commended the scientists and Division staff for their research and their ability to see where the field has been going, and although she expressed disappointment that a cure for AD has not yet been found, she was excited to see that more is known about the initiation and progress of the diseases. Dr. Morrison-Bogorad also commended NIA for the way its components are interconnected and work well together. She said she has enjoyed working with the Council, and she acknowledged members’ insightful questions and sage advice.
Laboratory of Genetics
Dr. Minoro Ko (Senior Investigator, Developmental Genomics and Aging Section) presented on research which uses a systems biology approach toward regenerative medicine. One major goal in the field is to identify ways to differentiate embryonic stem cells (ESCs) or induced pluripotent stem cells (IPS) into desired cell types. Dr. Ko’s section has specifically studied the manipulation of various transcription factors. The section has derived 145 ESC lines, which are available from Coriell Cell Repositories.
ESCs have remarkable abilities, including the ability to grow and divide indefinitely, without undergoing crisis or transformation. A systematic analysis of pre-implantation mouse embryos revealed Zscan4, a transcription factor specific to two-cell mammalian embryos. Of 250 transcription factors analyzed by Dr. Ko’s section, Zscan4 is one of only two factors with a unique expression pattern. Whereas other key developmental genes are expressed homogenously, Zscan4 is expressed only in 5 percent of ESCs at any point in time. However, through cell sorting using transgenic constructs of Zscan4, Dr. Ko’s group has found that eventually all ESC descendants have expressed Zscan4 at some point in time, and that Zscan4 expression is reversible and transient.
This intermittent, transient expression of Zscan4 is required for the immortality of ESCs. In knockdown experiments where Zscan4 expression is blocked, ESCs appear normal, but their proliferation eventually slows down, and only a small percentage of them show normal karyotypes. Telomere shortening, which is associated with cellular senescence, is one mechanism involved in the karyotype deterioration seen in Zscan4-knockdown cells. Yet the involvement of Zscan4 in telomere extension is independent of telomerase. Overexpression of Zscan4 promotes telomere recombination or telomere sister chromatid exchange, indicating that Zscan4 promotes telomere extension through a poorly understood, alternative mechanism for telomere lengthening. Moreover, Zscan4 colocalizes with meiosis-specific proteins.
These results suggest a model in which Zscan4 is a master gene that provides ESCs with immortality and the ability to defy senescence, maintain telomeres, maintain genome integrity, and maintain normal karyotypes. They also challenge the widely accepted definition of ESCs as a fountain of youth that can produce unaltered daughter cells. On the basis of Dr. Ko’s data, ESCs might gradually lose telomere length and other features with each cell division, until they reach a point where Zscan4 expression is turned on to restore them to their original state. Thus ESCs might not have the capacity for self-renewal so much as rejuvenation.
Dr. Ko acknowledged that these studies had been done with mouse ESCs in cell culture, giving rise to a concern that these observations could be an artifact. However, recent studies have found that Zscan4 is present and active in human cells, particularly in a rare population that might represent tissue stem cells. Because the human body is maintained by tissue stem cells, mechanisms that activate Zscan4 might yield clues for interventions that extend longevity.
In response to questions from Dr. Hodes, Dr. Ko noted that it is not clear how the telomerase-independent action of Zscan4 can be reconciled with maintenance of germline ESCs, which depends on telomerase. Other questions focused on technical aspects of this work.
Brain, Physiology, and Metabolism Section
Dr. Stanley Rapoport (Chief, Brain Physiology and Metabolism Section) presented on studies of the fatty acid arachidonic acid (AA) and its role in neuroinflammation. Lipopolysaccharide (LPS)-induced activation of the microglia in the central nervous system leads to the production of pro-inflammatory cytokines and the activation of AA-specific phospholipase A2, which releases AA from the cell membrane and induces a cascade leading to cell death and neuronal dropout. Dr. Rapoport’s section has developed an in vivo method to measure AA metabolism, which is upregulated during neuroinflammation. They have further found that lithium and three mood stabilizers approved for treatment of bipolar disorder downregulate the AA cascade and are thus neuroprotective. Moreover, postmortem studies show marked neuroinflammation, associated with upregulation of AA-specific phospholipases, in the brains of individuals who had bipolar disorder.
The Brain, Physiology, and Metabolism Section also has examined HIV1 infection as a model of progressive neuroinflammation, working with a transgenic rat model in which HIV1 does not express its infectivity genes but still expresses the microglial activator gp120. At 7 to 9 months of age, expression of cytokines, other markers of microglial activation, and AA-specific phospholipases is increased, and neuroimaging shows a 100 percent increase in the incorporation of AA. These results are of particular importance to the National Institute of Allergy and Infectious Diseases (NIAID), which is working to understand HIV-associated dementia. NIAID has initiated a clinical protocol to measure AA and blood flow in HIV-infected patients and determine whether these measures can be associated with severity of dementia.
These studies suggest neuroinflammation as a therapeutic target in bipolar disorder and HIV-associated dementia. Studies are under way to examine neuroinflammation as a biomarker and possible therapeutic target in AD and other progressive brain diseases. Other studies are examining the effects of mood stabilizers, non-steroidal anti-inflammatory drugs (NSAIDs), liver X receptor antagonists, and specific diets on neuroinflammation.
Dr. Mucke commented that in 2008, he and his colleagues reported links between apoE4 peptides and group 4 phospholipase A2, as well as the overlap between those findings and the data presented by Dr. Rapoport regarding bipolar disorder. Dr. Rapoport pointed out that in addition to cognitive decline, depression and behavioral changes are also present in AD, bipolar disorder, and HIV-associated dementia. It is likely that these characteristics could be alleviated by interventions that address neuroinflammation.
In response to questions from Dr. Hodes, Dr. Rapoport noted collaboration with a Department of Veterans Affairs site in Boston to look at links between NSAID use and admissions for suicide attempts. Other Council questions focused on myo-inositol as another potential neuroinflammation marker and technical aspects of the work presented by Dr. Rapoport.
This portion of the meeting was closed to the public in accordance with the provisions set forth in Section 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).
The open session of the 112th meeting of the National Advisory Council on Aging adjourned at 1:33 p.m. on January 26, 2011. The next meeting is scheduled for May 24 and 25, 2011.
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 May 24–25, 2011, 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)(**Provisional member whose appointment is not yet official)
Richard J. Hodes, M.D.
Director, National Institute on Aging
National Institutes of Health
Lisa F. Berkman, Ph.D. (2011)
Director and Professor
Harvard School of Public Health
Dept of Society, Human Development, and Health, and Dept of Epidemiology
Dale E. Bredesen, M.D. (2011)
Buck Institute for Age Research
Robert M. Califf, M.D. (2013)
Vice Chancellor for Clinical Research, Duke University
Director, Duke Translational Medicine Institute
*Peggye Dilworth-Anderson, Ph.D. (2011)**
Professor, Health Policy & Management
Associate Director, Aging and Diversity/ Institute on Aging
University of North Carolina, Chapel Hill
Chapel Hill, NC
*Hendrie, Hugh C., MB, ChB, DSC (2013)
Professor, Department of Psychiatry, Indiana University School of Medicine
Research Scientist, Regenstrief Institute, Inc.
Center Scientist, Indiana University Center for Aging Research
*S. Michal Jazwinski, Ph.D., (2011)**
Department of Medicine
Tulane University Health Sciences Center
New Orleans, LA
*Sundeep Khosla, M.D. (2011)**
Professor, Endocrine Research Unit
Division of Endocrinology, Metabolism, & Nutrition
Mayo Clinic College of Medicine
*Andrea Z. LaCroix, Ph.D., M.P.H. (2012)
Fred Hutchison Cancer Research Center
Women’s Health Initiative Clinical Coordinating Center
Victor Molinari, Ph.D. (2012)
University of South Florida
Department of Aging and Mental Health
*Lennart Mucke, M.D. (2012)
Director and Professor of Neuroscience
Gladstone Institute of Neurological Disease
University of California, San Francisco
San Francisco, CA
Perry, Daniel P. (2013)
President and CEO
Alliance for Aging Research
Washington, DC 20006
Petersen, Ronald C., M.D., Ph.D. (2013)
Professor of Neurology
Cora Kanow Professor of Alzheimer’s Disease Research
Director, Mayo Alzheimer’s Disease Research Center
Director, Mayo Clinic Study of Aging
*Orien Reid (2011)**
Chairman, Alzheimer's Disease International
President, Consumer Connection
*Richardson, Arlan G., Ph.D. (2013)
Barshop Institute for Longevity and Aging Studies
University of Texas Health Science Center
San Antonio, TX
June Simmons (2012)
Chief Executive Officer
Partners in Care Foundation
San Fernando, CA
James P. Smith, Ph.D. (2011)
Department of Labor and Population
Santa Monica, CA
*Susan L. Swain, Ph.D. (2011)
Department of Pathology S2-137
University of Massachusetts Medical School
Worcester, MA 01655
*Wetle, Terrie F., Ph.D. (2013)
Associate Dean and Professor
Program in Public Health
Division of Biology and Medicine
EX OFFICIO MEMBERS
Department of Health and Human Services
Hubert H. Humphrey Building
Francis S. Collins, M.D., Ph.D.
National Institutes of Health
Public Health Service
James F. Burris, M.D.
Geriatrics & Extended Care Strategic Healthcare Group
Department of Veterans Affairs
Deputy Assistant Secretary for Policy and Management
U.S. Department of Health and Human Services
Administration on Aging
Kenneth G. Pugh, M.D.
Commander, MC, U.S. Navy
U. S. Naval Hospital Rota
PSC 819 Box 18-74