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Council Minutes - September 2015

The 126th Meeting
September 16–17, 2015

CONTENTS

  1. REVIEW OF APPLICATIONS
  2. CALL TO ORDER
  3. REPORT: Task Force on Minority Aging Research
  4. REPORT: COUNCIL OF COUNCILS
  5. FINAL REPORT: DGCG PROGRAM REVIEW
  6. REPORT: WORKING GROUP ON PROGRAM
  7. COUNCIL SPEAKER: THE NIH STRATEGIC PLAN
  8. COMMENTS FROM RETIRING COUNCIL MEMBERS
  9. PROGRAM HIGHLIGHTS
  10. ADJOURNMENT
  11. CERTIFICATION

Attachment A: Roster of the National Advisory Council on Aging
Attachment B: Director's Status Report to Council
Attachment C: January 2015 minutes in PDF format (155K)

The 126th meeting of the National Advisory Council on Aging (NACA) was convened on Wednesday, September 16, 2015, at 3 p.m. in Building 31, Conference Room 10, National Institutes of Health (NIH), Bethesda, MD. Richard J. Hodes, M.D., 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 16, from 3 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 92–463.1The meeting was open to the public on Thursday, September 17, from 8 a.m. to 1:15 p.m.

Council Participants:

Dr. Kimberly Acquaviva
Dr. Maria C. Carillo
Dr. Laura Carstensen
Dr. Ana M. Cuervo
Dr. Steven R. Cummings
Jennie C. Hansen
Dr. Kevin P. High
Dr. Bradley T. Hyman
Dr. James L. Kirkland
Dr. Eliezer Masliah
Dr. Richard Mayeux
Dr. Charles P. Mouton
Dr. Anne B. Newman
Dr. Thomas A. Rando
Dr. Reisa A. Sperling
Dr. Debra Bailey Whitman

Absent Council Members:

Dr. Jonathan S. Skinner

Ex Officio Participants:

Dr. Richard M. Allman, Veterans Health Administration
Dr. Jane Tilly, Administration for Community Living

Absent Ex Officio Participants:

Dr. Kenneth G. Pugh, National Naval Medical Center
Edwin L. Walker, Administration on Aging

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. Valerie Durrant, Center for Scientific Review (CSR)
Dr. Kate Fothergill, CSR
Dr. Yuan Luo, CSR
Dr. Suzanne Ryan, CSR
Dr. Lawrence Tabak, Deputy Director, NIH
Dr. Wei-Qin Zhou, CSR

Members of the Public Present:

James Appleby, Gerontological Society of America
Trish Dantonio, Gerontological Society of America
Dr. Vishwa Deep Dixit, Yale School of Medicine
Guy Eakin, BrightFocus Foundation
DaShawn Fleming, National Capitol Contracting
Dr. Chandra Keller-Allen, Rose Li and Associates, Inc.
Dr. Kostas Lyketsos, Johns Hopkins School of Medicine
Dr. Frances McFarland Horne, Rose Li and Associates, Inc.
Dr. J. Michael McWilliams, Harvard Medical School

  1. REVIEW OF APPLICATIONS

This portion of the meeting was closed to the public, in accordance with the determination that it concerned matters exempt from mandatory disclosure under Sections 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).1

A total of 1228 applications requesting $23,211,385,895 for all years underwent initial review. The Council recommended 669 awards for a total of $14,046,998,531 for all years. The actual funding of the awards recommended is determined by the availability of funds, percentile ranks, priority scores, and program relevance.

  1. CALL TO ORDER

Dr. Hodes welcomed members to the open session of the 126th NACA meeting and called the meeting to order at 8 a.m. on Thursday, September 17, 2015.

  1. Director’s Status Report

Dr. Hodes reminded the Council that, with corrections for biomedical inflation rates, the overall NIH budget has suffered a precipitous drop and some recovery during the past decade. He also noted that the recovery for NIA has outpaced that for NIH, primarily because of the increase in funds specifically for Alzheimer's Disease (AD) research. The FY2016 budget has not been determined yet. The language from both the House and Senate appropriations committees increase the overall NIH budget, with $300 million to $350 million for AD research. It is not clear whether these increases will appear in the final budget. At best, there will be a continuing resolution in place at the start of the new fiscal year.

Payline: General/Alzheimer's
  <500 K: General <500 K: AD >500 K: General >500 K: AD
Payline
8
17
5
14
New Investigators (R01)
12
21
9
18
Early Stage Investigators (R01)
14
23
11
20

Dr. Hodes explained the payline for general research and for research on Alzheimer's disease as shown in the above table.  Dr. Hodes cited the overall increase in high-scoring applications, resulting in part from changes in resubmission policies, as the primary reason for the drop in general payline from last year. He also noted difficulties in planning for 2016 in light of the uncertainties about the budget.

Congress also has directed NIH to submit a bypass budget as an illustration of what would be necessary to carry out the research needed to meet the goals of the National Plan to Address Alzheimer's Disease. A draft bypass budget has been developed with the input of many, including directors from 13 Institutes and Centers (ICs). Dr. Hodes reminded the Council that there are only two other NIH bypass budgets—one for cancer research and one for HIV/AIDS. However, unlike the others, the bypass budget for AD research is tied to specific milestones. The draft bypass budget estimates a baseline of $638 million needed for AD, $46 million for vascular cognitive impairment and dementia, $38 million for frontotemporal dementia, and $15 million for Lewy body dementia. Dr. Hodes pointed out that these estimates are not additive and that there are some overlaps based on Research, Condition, and Disease Categorization (RCDC). For FY2017, NIH estimates that an increase of $323 million will be needed.

The bypass budget estimates, along with a narrative, have been available for public comment since July. The bypass budget will be submitted to Congress for its deliberations on the FY2017 budget and it is likely that NIH and NIA leadership will be called to discuss it. Dr. Hodes pointed out that NIH and NIA intend to be agile and responsive and to ensure that any increase appropriated in FY2016 does not preclude increases needed for future years.

Dr. Hodes highlighted studies that have received recent attention. The Systolic Blood Pressure Intervention Trial (SPRINT), which was supported by the National Heart, Lung, and Blood Institute, NIA, the National Institute of Diabetes and Digestive and Kidney Diseases, and the National Institute of Neurological Diseases and Stroke (NINDS), was stopped 1 year early because of significant findings. This randomized controlled trial of more than 9,000 participants aged 50 years and older (about a quarter were aged 75 years and older) found that adjusting medications to achieve a systolic blood pressure target of 120 decreased the risk for cardiovascular events and stroke by almost a third and mortality by almost a quarter, compared with a target of 140. Preliminary analyses so far suggest similar effects in all population subgroups, including older adults. Dr. Hodes highlighted two studies on caloric restriction. One, the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE), was discussed later in the day by Evan Hadley, M.D., of NIA. Another, published by Sebastian Brandhorst, Ph.D., and colleagues in Cell Metabolism (22: 86-99, 7 July 2015), explored strategies for intermittent fasting. Dr. Hodes also noted a recent randomized controlled trial assessing financial incentives as strategies for smoking cessation published by Scott Halpern, Ph.D., and Kevin Volpp, Ph.D., both NIA grantees, and colleagues in the New England Journal of Medicine (372: 2108-2117, 28 May 2015), which was supported by the NIH Science of Behavior Change Common Fund Program. In addition, Dr. Hodes reminded the Council about major AD research initiatives, including the AD Neuroimaging Initiative and the Accelerated Medicines Partnership, and highlighted a recent advance in tau imaging.

Dr. Hodes noted the success of the 2015 Butler-Williams Scholars program and the publication of the Health Disparities Framework developed by the Task Force on Minority Aging. He reported that the Aged Animal Colony, which had stopped charging users because of a new interpretation of regulations governing contracting, has seen a large increase in demand, particularly for C57BL/6 mice. NIA is scaling up, but the impact on availability will not be realized for 2 years. A more detailed report will be presented at the January Council meeting. Dr. Hodes concluded his report by noting that Walter Koroshetz, M.D., had been named director of NINDS; former NACA member, Eliseo Perez-Stable, M.D., had been named director of the National Institute on Minority Health and Health Disparities; and Sally Rockey, M.D., is leaving her position as NIH deputy director for Extramural Research. He also invited Council members to review and comment on proposed updates to the Common Rule.

Finally, Dr. Hodes recognized the extraordinary service of Neil Buckholtz, Ph.D., director of the Division of Neuroscience, who will be leaving NIA.

In response to questions from Council, Dr. Hodes reported that the bypass budget is used to guide Congressional deliberations on appropriations beyond the baseline NIH budget.

Richard Mayeux, M.D., also reported that the AD Sequencing Project, which is supported by NIA, has almost completed sequencing. Results are expected to be available by early spring 2016.

  1. Future Meeting Dates

January 19–20, 2016 (Tuesday and Wednesday, Building 31)
May 10–11, 2016 (Tuesday and Wednesday, Building 31)
September 27–28, 2016 (Tuesday and Wednesday, Building 31)

  1. Consideration of Minutes of the Last Meeting

The minutes of the May 2015 meeting were considered. A motion was made, seconded, and passed unanimously to approve the minutes.

  1. REPORT: TASK FORCE ON MINORITY AGING RESEARCH

Ana Maria Cuervo, Ph.D., reported that the Task Force heard two talks. The first was given by Duke Han, Ph.D., of the Rush Alzheimer's Disease Center, who has used high-quality neuroimaging to explore cognition and decision-making in aging. Decision-making is of particular interest because older adults are often susceptible to scams and because impaired decision-making can be an early sign of AD. In one study, Dr. Han and his colleagues used neuroimaging to look at decision-making in financial risk aversion, temporal discounting, financial literacy, and susceptibility to scams. Surprisingly, they found that poor decision-making is not always associated with mild cognitive impairment; contextual factors also appear to be involved. This was especially true for older black individuals, who showed lower susceptibility to scams despite poorer decision-making.

The second talk was given by Frances Carter-Johnson, Ph.D., a consultant with the NIH Division of Biomedical Research Workforce who is examining administrative data to better guide scientific and workforce policy decisions. Dr. Carter-Johnson introduced the work of the Division, which was created in response to a publication describing racial and ethnic bias in NIH research awards. The Division of Biomedical Research Workforce aims to increase understanding about innovation as a function of diversity or bias by clarifying definitions through collaboration; by exploring and using national-level census, scientific, and innovation data; and by synthesizing study results. For example, the Division has used census data to describe the gender and racial/ethnic composition of the workforce. It has linked patent data with data from the National Science Foundation to follow successful individuals who have not received NIH funding.

Dr. Cuervo discussed the Butler-Williams scholars program, a blog aimed toward informing basic scientists about the challenges and possibilities related to health disparities research, and publication of the health disparities framework generated by the Task Force's 2011 review. The Task Force also heard a report on the NIH Women of Color Research Network from Cerise Elliot, Ph.D., who has been recognized by NIA staff for her extraordinary efforts.

In response to questions from Ms. Jennie Hansen about applying the knowledge gained from Dr. Han's studies, Debra Bailey Whitman, Ph.D., reported that AARP was talking with Dr. Han and this research was helpful to the Association in understanding issues of financial literacy and in dispelling powerful stereotypes. Dr. Cuervo also noted that Dr. Han has emphasized the NIA-supported training he had received, for example, as a Beeson scholar and as a Butler-Williams scholar, as fundamental contributions to his career.

  1. REPORT: COUNCIL OF COUNCILS

Dr. Cuervo reported on the June and September meetings of the NIH Council of Councils (CoC). The CoC, which had been conducting second-level reviews for the Common Fund and Early Independence Awards, will now conduct reviews for the Pioneer and New Innovator awards. Dr. Cuervo highlighted new proposals for Common Fund support, including a program focusing on the –omics associated with short-term exercise and one enabling exploration of the eukaryotic epitranscriptome. The CoC also has cleared a concept for the Kids First Program, which will make all information and databases related to pediatric health compatible and develop a common database focused on structural birth defects and pediatric cancer data. This concept will be submitted for approval at the January CoC meeting. Renewed Common Fund programs include Illuminating the Druggable Genome, which is systematically generating knockout mice to define the function of genes across the mammalian genome. The program is adopting the CRISPR CAS9 technology to generate knockouts and there has been some discussion about conditional models and what will happen once the project sunsets.

The Common Fund is contributing to another activity that is exploring ways to facilitate data mining of the datasets generated by research communities. Biomedical research is moving into Big Data more quickly than anticipated, but how to handle such enormous amounts of data is still unclear. The Big Data to Knowledge (BD2K) program, which has made awards to 12 centers, aims to ensure that existing databases can communicate, bring together communities to solve problems, and establish policies for new strategies in data-sharing and reporting. Pilot projects are under way to determine if this strategy is efficient.

Activities outside the Common Fund include efforts to enhance research core facilities. The American Recovery and Reinvestment Act Core Consolidation Supplement Program, which began in 2009 with the participation of 12 ICs, has funded 26 applications out of 80 received. Overall, awardees have found that consolidation increases the number of core facility users, improves and increases revenue to support more personnel and services, decreases overall expenses, and increases productivity. NIH also held a workshop to generate recommendations for further improvement.

Dr. Cuervo closed by reporting on a presentation by the director of the National Institute of General Medical Sciences, who described the Maximizing Investigators Research Award (MIRA), which is similar to the Pioneer Award. The award is not based on specific aims but on the research idea and the investigator's track record, service, and contribution to training. Different review panels are in place for younger investigators. The Request for Applications has posted, but it is not yet clear how many applications have been submitted. Many junior investigators are in the applicant pool. Although there is still some confusion about metrics, there is general agreement that success should not be measured by the number of papers.

Dr. Hodes added that in Illuminating the Druggable Genome program, mice were tracked only through 16 weeks and sacrificed if they showed no evidence of a phenotype. However, evidence suggests that some phenotypes do not emerge until later in life. A proposal to follow the mice for longer than 16 weeks has received support from the ICs and has been presented to the Common Fund.

With respect to BD2K, Dr. Whitman asked about policy development around privacy. As databases are merged, investigators might have access to information that might not have been included in the initial consent documents. Dr. Cuervo responded that the pilot experiments in BD2K are voluntary and that investigators will build in strategies for data sharing.

In response to questions from Eliezer Masliah, M.D., Dr. Cuervo noted that the National Cancer Institute has an initiative similar to MIRA. Dr. Hodes noted that NIA had discussed such an initiative but had decided to wait for early outcomes from other initiatives. He suggested that this topic be discussed at a future Council meeting.

  1. FINAL REPORT: DGCG PROGRAM REVIEW

Kevin High, M.D., reviewed the organization and goals of the Division of Geriatrics and Clinical Gerontology (DGCG), which represents about 12 to 13% of the NIA budget and funds a similar proportion of NIA research grants. He reported that the 2015 review committee had reviewed DGCG's response to the report from the 2010 review committee. Overall, the Division had been highly responsive to the suggestions from that committee and it did particularly well in focusing on vulnerability, multimorbidity, and health span rather than lifespan. However, DGCG had not focused as much on pathologies affecting older adults or translational work with other NIA Divisions, particularly on potential circulating pro- and anti-aging factors. Although DGCG had made progress toward identifying biomarkers, surrogate markers, and composite markers, more work was needed in Big Data. Among the Division's response to the 2010 review committee's suggestions for training, the most successful effort has been the Grants for Early Medical/Surgical Specialist Transition to Aging Research (GEMSSTAR) program.

The 2015 committee made the following broad recommendations:

  • Accelerate translational efforts through trans-NIA collaborations with other Divisions, a mechanism to bring together directors from NIA-supported and non-NIA-supported Centers, and development of a minimal phenotyping dataset both for aging-appropriate phenotyping and for electronic medical record (EMR) integration.
  • The critical need for continued development of appropriately trained investigators is particularly problematic for DGCG, where clinician-investigators are crucial but scarce and declining. Address critical training gaps through continued support of GEMSSTAR; expanded engagement in T35, MD/PhD, Butler-Williams, and other programs; partnering with Clinical and Translational Science Award centers (CTSAs) to increase aging "slots"; and developing and promoting a Howard Hughes-like program to have investigators spend 6 to 12 months in the NIA Intramural Research Program.
  • Leverage partners by supporting interactions between CTSAs and NIA-supported Centers, leveraging the work of the trans-NIH Geroscience Interest Group, encouraging development of knitted cohort designs to merge cohorts at various stages of life, increasing cooperation with industry and other partners, and joint efforts with the Patient-Centered Outcomes Research Institute (PCORI) and the health care industry.
  • Develop additional strengths in new research paradigms, such as other –omics and Big Data/EMR research.
  • Address problems with grant solicitation and review. DGCG receives only 12 to 13% of the applications submitted to NIA and these applications do not fare as well at the Center for Scientific Review, primarily because of their complexity. DGCG can address these problems by continuing to reform and refine the Clinical Trials Advisory Panel and by issuing Program Announcements with special receipt, referral, or review considerations.

Ms. Hansen emphasized the need to consider the importance of a sense of community among young investigators and changes in social culture as DGCG addresses training. She noted that complexity is always a feature of geriatrics—and of human health overall—and that reviewers should be able to consider it and she asked whether groups of methodologists existed to bridge the gap from the kind of research accepted in journals to "real outcome work." Dr. High noted that PCORI has a methodology subgroup and that groups through many NIA Centers include biostatisticians and experts in study design.

A motion to approve the final report of the DGCG Review Committee was made and seconded. The motion passed unanimously.

  1. REPORT: WORKING GROUP ON PROGRAM

  1. Working Group on Physician-Scientist Training

Dr. High presented the final report from the Task Force on Physician-Scientist Training. This task force was formed in response to NIA's concerns that K award applications were declining because some of these programs were losing relevance. The task force examined reasons for the decline in applications, how well K awards promote clinical careers in research, and any changes that should be considered.

The task force found that among the 2,000 applications received from 2002 through 2014, the number of K award applications from Ph.D.s increased steadily. In contrast, the number of applications from M.D.s and M.D./Ph.D.s declined. The majority of applications were for K23 and, more recently, for K08, but even with these awards, the number of applications was declining. Whereas Ph.D.'s applying for K awards applied for the K99/R00, this award mechanism was not applicable to M.D.s and M.D./Ph.D.s because of time constraints and the portability of the grant. The task force found that the number of K award applications from physician-scientists was declining because of uncertainties with a grant-funded career, the average salary for physician-scientists outpace compensation supported by K awards, and departments are increasingly unable to fill the pay gap.

About half of M.D.s secured a K award before they receive their first R01, compared with approximately a third of M.D./Ph.D.s and only 6% of Ph.D.s. However, for M.D.s, securing a K award shortened the time from the doctoral degree to the first R01 from 18 years to 16 years. Thus, although the mentored K award remains a valuable mechanism for training physician-scientists, fewer than half of M.D.s and M.D./Ph.Ds are using it.

On the basis of these data, the task force made the following recommendations:

  • Increase the dollar amount for each K award to cover the same percentage of salary that was covered in 1996. However, the total number of K awards should not decrease.
  • Allow a step-down K award that allows for less than 75% of effort to be charged to the award. Such a structure would require 75% of protected time in year 1 but would allow reductions in later years.
  • Foster creative ways of continuing the K-initiated research programs, for example with a more M.D.-friendly K99/R00 award.
  • Take advantage of strategically designed pre-K awards to facilitate an expansion of the physician-scientist pipeline. NIA has been a pioneer in such awards.
  • Make periodic reports to NACA on new NIA-funded R01 investigators, including M.D.s, M.D./Ph.D.s, and Ph.D.s.

A motion to accept this report was made and seconded. The motion passed unanimously.

  1. Other Items

Robin Barr, D. Phil, announced that Dr. Mayeux will chair a committee that will review extramural research across NIA. Dr. Barr also thanked the Council for its expedited review of concept clearances for AD funding opportunity announcements.

  1. COUNCIL SPEAKER: THE NIH STRATEGIC PLAN

In December 2014, Congress enacted legislation calling for NIH to submit a 5-year strategic plan no later than 1 year following enactment. In addition, a section of pending legislation, the 21st Century Cures Act, calls for the development and maintenance of a 5-year strategic plan for biomedical research. This plan should identify research opportunities and develop individual strategic plans, with a common template, for the research activities of each IC. It should identify strategic focus areas with a focus on return on investment, ensure that rare and pediatric diseases remain a priority, and ensure that maintaining a biomedical workforce remains a priority. In response, NIH aims to develop a strategic plan that is a "living document" to guide it in fulfilling its mission over the next 5 years, articulate forward-looking and inspirational approaches and opportunities, and identify major trans-NIH themes that will advance biomedical research. The strategic plan will not describe the many activities of NIH or address the priorities of the individual ICs.

Lawrence Tabak, Ph.D., principal deputy director, NIH, described the process for developing the plan and presented an overview of the draft. The process involved discussions with NIH senior leadership, involvement of IC representatives in a working group, and review of the draft plan and input from the NIH Advisory Council to the director. The draft strategic plan is organized into the following sections:

  • An overview articulating the agency mission and noting the unique moment in the history of biomedical research while acknowledging the realities accompanying the lost purchasing power in the NIH budget.
  • Areas of opportunity that apply across biomedicine, with a succinct description of each emergent opportunity, what NIH should do to realize those opportunities, specific examples of breakthroughs, and ways in which the opportunity aligns with the Department's strategic plan. These areas include fundamental science, health promotion and disease prevention, and treatments and cures.
  • Unifying principles such as priority-setting and enhancing stewardship.

NIH is conducting extensive outreach to shape the strategic plan. A Request for Information, which closed in mid-August 2015, received 460 responses. Most were positive. However, there were broad suggestions to emphasize implementation and interdisciplinary science and to improve the peer review process and there were specific suggestions to promote use of Big Data, emphasize population health, and adopt a greater focus on mental illness. NIH also has conducted three webinars and received feedback that patients should be partners and not subjects and that the strategic plan should be more explicit about including behavioral and social science research. Dr. Tabak is now presenting the draft strategic plan to the IC advisory committees. He invited Council members to ask questions or to email him directly.

In response to questions from Reisa Sperling, M.D., Dr. Tabak acknowledged that, to maximize public investment, the strategic plan will need to address the tension between smaller discovery projects and big scientific projects that will speed the translation of discoveries to patients. However, he noted that no algorithm exists to set the right ratio. Dr. Masliah noted the increasing complexity of science and the emergence of new types of applications and he suggested that the strategic plan include efforts to simplify application and review processes. Other Council members noted the need to emphasize public-private partnerships and collaboration with existing efforts overseas, include multimorbidity to reflect real patients, facilitate collaboration among existing cohort studies across ICs, promote collaboration with willing partners in industry, and include sections for applicants to address the inclusion of older populations in their studies as they currently are required to do with minority populations.

  1. COMMENTS FROM RETIRING COUNCIL MEMBERS

Dr. Hodes recognized three outgoing members. One, Jonathan Skinner, Ph.D., was not present at the meeting.

Laura Carstensen, Ph.D., expressed gratitude at being part of the scientific community at a time of breathtaking opportunity. She noted NIH as the reason for the Nation being second to none in science and she recognized NIH's review process, depth of intelligence, and efforts to improve and ensure that scientists sample from the entire pool in the country. Dr. Carstensen pointed out that to study aging, one has to be interested in multidisciplinary research, because an organism changes as it ages, in ways that cuts across traditional research boundaries. She acknowledged how much she has learned as a member of Council and she recognized the remarkable staff in the Division of Behavioral and Social Research (DBSR) where her research resides. She closed her remarks by recognizing the late Richard Suzman, Ph.D.

Dr. Cuervo stated that she had received more from NIA than she had contributed and that she was grateful for the opportunity to serve on Council. She noted the tough times NIA had endured, such as the sequester and difficulties with the colony of aging animals, but she also highlighted opportunities such as the trans-NIH Geroscience Interest Group. Dr. Cuervo noted the ability to see how NIA leadership and program staff work and to speak with younger investigators after each meeting as particular benefits of serving on the Council.

  1. PROGRAM HIGHLIGHTS

  1. Division of Neuroscience (DN): Advances in Treating Agitation in Alzheimer Dementia: Lessons from the CitAD Study

Constantine Lyketsos, M.D., of Johns Hopkins University, presented findings from the Citalopram for Agitation in AD (CitAD) study, which were published in JAMA in 2014. Although AD is generally understood as a memory disorder, memory problems are a minor part of the disease. Neuropsychiatric symptoms such as agitation are universal, most treatable, and likely a prodrome of AD dementia. They also have serious adverse effects on quality of life for the patient and are the largest source of burden on the caregiver; thus they are a major driver of institutionalization among patients with AD. Development of these symptoms early in the course of AD appears to accelerate severe dementia and even death. Thus, treating these symptoms may have a large impact on patient care. The U.S. Food and Drug Administration (FDA) now accepts phenotypic classifications of these symptoms as indications for new treatments.

One such symptom, agitation, is a phenotype comprising emotional agitation, changeability, psychomotor activity, and verbal or physical aggression. Pharmacological options for agitation have been disappointing. Anti-psychotic drugs remain the mainstay but they still have a black box warning, and with the exception of citalopram, anti-depressive drugs do not appear to be effective. Little time has been spent on non-pharmacological interventions. Few studies have assessed the effectiveness of non-pharmacological interventions, which are also important.

In the trial described by Dr. Lyketos, 186 patients with AD and agitation received a simple psychosocial intervention in combination with 300 mg per day citalopram or placebo for 9 weeks. Patients were monitored by electrocardiogram (EKG) because of FDA warnings about QTc prolongation at higher citalopram doses. Patients received mirazopam as needed. The response rate was 40% among patients receiving citalopram, compared with 20% among those receiving placebo, indicating that citaloprom provided only a small benefit. In addition to QTc prolongation, common adverse events associated with citalopram included anorexia, diarrhea, and fever.

The trial yielded several lessons. There were differences between groups in the timing of response. Whereas all patients who would respond in the placebo group did so by 3 weeks of treatment, the number of patients responding in the citalopram group continued to accumulate throughout the 9-week treatment period. Although the proportion of patients experiencing delusions did not change significantly in the citalopram group at the end of 9 weeks, symptom severity did decline in the citalopram group. Pharmacokinetic and pharmacodynamic studies showed that R-citalopram was associated primarily with EKG abnormalities and worsening cognition, whereas symptom severity reduction was associated primarily with S-citalopram. In addition, agitation is a heterogeneous phenotype. CitAD investigators developed an index based on baseline characteristics and found that patients in the ninth and tenth tertiles had a clear and robust response to citalopram. Further assessment of this subgroup allowed investigators to identify high affective symptoms and loss of executive control as potential predictors of response. Future plans include further exploration of a precision medicine approach and development of a sequential algorithm for treating agitation.

  1. Division of Aging Biology (DAB): Harnessing Immune-Metabolic Interactions to Enhance Healthspan

Dr. Vishwa Dixit, Ph.D. of the Yale School of Medicine, described work in his laboratory examining immune-metabolic interactions.  As early as the early 20th century, Elie Meshnikoff noted that phagocytes resist "poisons" and are even stimulated by them and that the changes induced by these poisons included deposition of fatty matter. One of these poisons, uric acid, increases with age and has been associated with the NLRP3 inflammasome, which includes caspase 1. Upon activation of the inflammasome by phagocytosis, caspase 1 is cleaved from the complex, promoting the release of IL-1b and IL-18. In animal models, removal of the inflammasome and its adaptor protein, ASC, results in attenuation of bone loss and protection from declines in cognition and the central nervous system. Dr. Dixit presented new data from studies investigating the metabolic and inflammatory changes that occur with caloric restriction.

Ketogenesis, or the production of ketone bodies, contributes to the adaptive starvation response and increases with increased use of lipids. Dr. Dixit and his colleagues have found that the ketone body metabolite b-hydroxybutyrate, which is elicited by caloric restriction, suppresses expression of the inflammasome in both young and old neutrophils by blocking oligomerization of the inflammasome adaptor ASC. This suppression does not require autophagy; rather, it works through a biophysical effect. Thus, b-hydroxybutyrate or a ketogenic diet might serve as interventions against age-related diseases driven by the NLRP3 inflammasome.  Dr. Dixit is extending his work to humans through secondary analyses of the CALERIE study.  Questions from the Council focused on potential inflammasome-related changes in the cerebrospinal fluid as a marker of activity in the brain.

  1. Division of Geriatrics and Clinical Gerontology (DGCG): CALERIE, a 2-Year Randomized Controlled Trial of Human Caloric Restriction's Feasibility and Effects on Predictors of Health Span and Longevity

Dr. Hadley discussed the CALERIE trial, a 2-year randomized controlled trial exploring the feasibility and safety of caloric restriction (CR), its effects on disease risk factors, and the biologic mechanisms underlying its effects. More than 200 non-obese individuals aged 21 to 50 years were randomized to caloric restriction or usual diet for 2 years. CR was defined as percent reduction in caloric intake from ad libitum habitual intake. The target for CALERIE was a 25% reduction and the study duration was long enough for participants to achieve a target and reach a stable weight (though not long enough to test the effects of CR on the rate of aging). Adherence was measured via DEXA to assess change in body stores and doubly-labeled water to assess carbon dioxide production, an estimate of energy expenditure. Participants also received a structured behavioral intervention over 2 years to help them achieve a target weight-loss trajectory. Primary outcomes were changes in body temperature and adjusted metabolic rate.

Whereas the control group did not lose weight, the CR group achieved a weight-loss trajectory at 6 months and sustained a 10% weight loss for 24 months. However, CR, though significant, did not reach 25%. Instead, participants achieved an average reduction of 12%. As investigators later learned, target weight-loss trajectories were inadequate to achieve the target CR. The proportion of adverse events was similar between the two groups, although there was a non-significantly higher rate of anemia in the CR group. CR had only a transient effect on residual resting metabolic rate and no significant effect on effective body temperature. However, triiodothyronine and TNF-alpha levels were significantly reduced at 24 months in the CR group. Other metabolic risk factors also decreased significantly. CR also was associated with a 2% decrease in bone mineral density, but this change did not appear to threaten health.

CALERIE is serving as a platform for future research; thus far it has generated 52 related publications, 3 ancillary studies, a database, and a biospecimen repository. Future CR studies may explore the possible extension of weight loss in preventive interventions in obese or overweight individuals, the identification of long-term predictors of CR effects on human lifespan, and the identification of potential targets for non-CR interventions in human aging.

Council discussion focused on the CALERIE biorepository and connections between this study and Dr. Dixit's work.

  1. Division of Behavioral and Social Research (DBSR): Improving Outcomes in the Medicare Program

J.  Michael McWilliams, Ph.D., of Harvard Medical School discussed efforts to improve outcomes in the Medicare program.  Payment and delivery reform in Medicare comprises five approaches. Medicare Advantage (MA) contracts with the insurer, places a cap on costs, and provides a strong incentive to improve the quality of care. With accountable care organizations (ACOs), Medicare contracts with the provider, sets a budget, and provides incentives to stay under budget while improving quality. Bundled payment initiatives set budgets for providers and thus focus more on cost than on quality. Pay-for-performance/value-based purchasing (P4P) weds specific quality and effectiveness measures with financial incentives. Advanced care models such as comprehensive care initiatives attempt to redesign the delivery system to support patient care without changing payment systems.

Dr. McWilliams and his colleagues have found lower resource use in the MA program than in traditional Medicare, particularly in inpatient settings and emergency department visits. MA also appears to be more efficient than traditional Medicare, and over time, is associated with substantially higher performance in terms of mammography, diabetes and cardiovascular care, and vaccination rates. Although it might appear that MA is more efficient because it attracts healthier patients, Dr. McWilliams' colleague, Katherine Baicker, Ph.D., found MA to be more efficient than traditional Medicare because of the strong incentives to minimize utilization and evidence of spillovers from MA to traditional Medicare programs. In another study, MA was found to be associated with significant improvements in disease control but it did not reduce persistent racial disparities except in the western United States, likely due to Kaiser Permanente deliberately reaching out to disadvantaged populations.

Dr. McWilliams and colleagues also have done work on risk adjustment and risk selection in MA using the HCC (Hierarchical Condition Categories) Risk Adjustment Model and the enrollment lock in, which was found to be associated with a substantial decline in the favorable risk selection that MA has traditionally enjoyed. An analysis of data from the Medicare Current Beneficiaries Survey found that utilization patterns and the percentage of beneficiaries in poorer health rose over time and overpayment resulting from favorable selection fell from $2,700 per beneficiary to $600 per beneficiary. However, residual favorable selection remains. Moreover, beneficiaries with higher cognition became more responsive as benefits became more generous, whereas those with lower cognition did not.

The group also has focused on ACOs. Dr. McWilliams and his colleagues found improvements in overall ratings of care, timely access to care, and management of care coordination. Thus improvements occurred in areas where providers can respond to financial incentives without training physicians or otherwise changing their behavior. However, there were no significant improvements in more physician-oriented measures, such as interactions with primary care physicians. The first year of the Pioneer ACO program saw a 1.2% reduction in Medicare spending. Almost 5% of those savings were related to low-value care. Thus, the ACO model generated modest savings without compromising measurable components of quality of care. However, the savings rose predominantly from ACOs situated in higher-spending areas or that were above-average for their area. Moreover, 13 ACOs that left this Pioneer program achieved comparable or higher savings than they would have had they stayed in the program.

Dr. McWilliams closed his presentation by noting work on the P4P model. Using data from the Health and Retirement Study, he and his colleagues have found that hospitals are being penalized to a large extent based on the type of patients they serve, rather than on the quality of care they provide, because Medicare currently considers a very limited set of characteristics when setting a hospital's readmission rate to judge its performance.

Council discussion focused on hospice use, the sources Dr. McWilliams and his colleagues used to derive their list of low-value services, changes in risk adjustment coding, and the potential impact of socioeconomic factors on hospital readmissions in rural areas.

  1. ADJOURNMENT

The open session of the 126th meeting of the National Advisory Council on Aging adjourned at 1:15 p.m. on September 17, 2015. The next meeting is scheduled for January 19-20, 2016.

  1. CERTIFICATION

I hereby certify that, to the best of my knowledge, the foregoing minutes and attachments are accurate and complete.4

 

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.

 

 

  1. For the record, it is noted that members absented themselves from the meeting when the Council discussed applications (a) from their respective institutions or (b) in which a conflict of interest may have occurred. This procedure only applied to applications that were discussed individually, not to “en bloc” actions. (Back to text)
  2. For the record, it is noted that members absented themselves from the meeting when the Council discussed applications (a) from their respective institutions or (b) in which a conflict of interest may have occurred. This procedure applied only to applications that were discussed individually, not to “en bloc” actions. (Back to text)
  3. 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 applied only to applications that were discussed individually, not to “en bloc” actions. (Back to text)
  4. These minutes will be approved formally by Council at the next meeting on January 19-20, 2016, and corrections or notations will be stated in the minutes of that meeting. (Back to text)

 

Attachment A: Roster of the National Advisory Council on Aging

MEMBERSHIP ROSTER
NATIONAL ADVISORY COUNCIL ON AGING
NATIONAL INSTITUTE ON AGING

MEMBERS

ACQUAVIVA, KIMBERLY DEANNE, PHD
ASSOCIATE DEAN FOR FACULTY AFFAIRS
ASSOCIATE PROFESSOR
SCHOOL OF NURSING
THE GEORGE WASHINGTON UNIVERSITY
WASHINGTON, DC 20036

CARRILLO, MARIA C, PHD
CHIEF SCIENCE OFFICER, MEDICAL & SCIENTIFIC RELATIONS
ALZHEIMER'S ASSOCIATION
NATIONAL OFFICE
CHICAGO, IL 60601

CUMMINGS, STEVEN RON, MD
FOUNDING DIRECTOR
SAN FRANCISCO COORDINATING CENTER
SAN FRANCISCO, CA 94109-1762

HANSEN, JENNIE CHIN, FAAN, RN
SENIOR STRATEGIC CONSULTANT
AMERICAN GERIATRICS SOCIETY
NEW YORK, NY 10038

HIGH, KEVIN P., MD
PROFESSOR AND CHAIR
DEPARTMENT OF INTERNAL MEDICINE
WAKE FOREST SCHOOL OF MEDICINE
WINSTON-SALEM, NC 27157

HYMAN, BRADLEY T., MD, PHD
PROFESSOR AND DIRECTOR
DEPARTMENT OF NEUROLOGY
ALZHEIMER'S RESEARCH
MASSACHUSETTS GENERAL HOSPITAL
CHARLESTOWN, MA 02129

KIRKLAND, JAMES L., MD, PHD
PROFESSOR
DEPARTMENT OF GENERAL INTERNAL MEDICINE
MAYO CLINIC
ROCHESTER, MN 55905

MASLIAH, ELIEZER, MD
PROFESSOR
DEPARTMENTS OF NEUROSCIENCES AND PATHOLOGY
UNIVERSITY OF CALIFORNIA, SAN DIEGO
LA JOLLA, CA 92093

MAYEUX, RICHARD P, MD
PROFESSOR
SERGIEVSKY PROFESSOR AND
CHAIRMAN, DEPT OF NEUROLOGY
COLUMBIA UNIVERSITY
NEW YORK, NY 10032

MOUTON, CHARLES P., MD
SENIOR VICE PRESIDENT & DEAN
DEAN, SCHOOL OF MEDICINE
MEHARRY MEDICAL COLLEGE
NASHVILLE, TN 37208

NEWMAN, ANNE B, MD
PROFESSOR
DEPARTMENT OF EPIDEMIOLOGY
UNIVERSITY OF PITTSBURGH
PITTSBURGH, PA 15213

RANDO, THOMAS A., MD, PHD
PROFESSOR
DEPARTMENT OF NEUROLOGY AND NEUROLOGICAL SCIENCES
STANFORD UNIVERSITY SCHOOL OF MEDICINE
STANFORD, CA 94304-5235

SPERLING, REISA A., MD
PROFESSOR OF NEUROLOGY
HARVARD MEDICAL SCHOOL
CENTER FOR ALZHEIMER RESEARCH & TREATMENT
MEMORY DISORDERS UNIT
BRIGHAM AND WOMEN'S HOSPITAL
BOSTON, MA 02115

WHITMAN, DEBRA BAILEY, PHD
EXECUTIVE VICE PRESIDENT, POLICY, STRATEGY, AND
INTERNATIONAL AFFAIRS
AARP
WASHINGTON, DC 20049

AD HOC

CRIMMINS, EILEEN M, PHD
AARP PROFESSOR OF GERONTOLOGY
DAVIS SCHOOL OF GERONTOLOGY
UNIVERSITY OF SOUTHERN CALIFORNIA
LOS ANGELES, CA 90089

KINGTON, RAYNARD S. M.D., MD, PHD
PRESIDENT AND PROFESSOR
GRINNELL COLLEGE
NOLLEN HOUSE
GRINNELL, IA 50112

MOFFITT, TERRIE E, PHD
NANNERL O. KEOHANE UNIVERSITY PROFESSOR
DEPARTMENT OF PSYCHOLOGY AND NEUROSCIENCE
DUKE UNIVERSITY
DURHAM, NC 27708

SHARPLESS, NORMAN E, MD
WELLCOME DISTINGUISHED PROFESSOR AND DIRECTOR
DEPARTMENT OF MEDICINE AND GENETICS
THE LINEBERGER COMPREHENSIVE CANCER CENTER
UNIVERSITY OF NORTH CAROLINA SCHOOL OF MEDICINE
CHAPEL HILL, NC 27599

EXECUTIVE SECRETARY

BARR, ROBIN, PHD
DIRECTOR
OFFICE OF EXTRAMURAL ACTIVITIES
NATIONAL INSTITUTE ON AGING
BETHESDA, MD 20814

EX OFFICIO

ALLMAN, RICHARD MARK, MD
CHIEF CONSULTANT
CENTER FOR AGING
UNIVERSITY OF ALABAMA AT BIRMINGHAM
BIRMINGHAM, AL 35294

BURWELL, SYLVIA M.
SECRETARY
DEPARTMENT OF HEALTH AND HUMAN SERVICES
WASHINGTON, DC 20201

COLLINS, FRANCIS S., MD, PHD
DIRECTOR
NATIONAL INSTITUTES OF HEALTH
BETHESDA, MD 20892
UNITED STATES

HODES, RICHARD J., MD
DIRECTOR
NATIONAL INSTITUTE ON AGING
NATIONAL INSTITUTES OF HEALTH
BETHESDA, MD 20892-2292

PUGH, KENNETH G.
LCDR, MC
DEPARTMENT OF MEDICINE
NATIONAL NAVAL MEDICAL CENTER
BETHESDA, MD 20889-5600

TILLY, JANE A, DRPH
AGING PROGRAM SERVICES SPECIALIST
TEAM LEADER, BRAIN HEALTH AND DEMENTIA
OFFICE OF SUPPORTIVE AND CAREGIVER SERVICES
ADMINISTRATION FOR COMMUNITY LIVING/ADMINISTRATION ON AGING
WASHINGTON, DC 20001

WALKER, EDWIN L
DEPUTY ASSISTANT SECRETARY FOR AGING
ADMINISTRATION ON AGING
ADMINISTRATION FOR COMMUNITY LIVING
DEPARTMENT OF HEALTH AND HUMAN SERVICES
WASHINGTON, DC 20201