SAGES NEWS. Sharon K. Inouye, MD, MPH. Wherever the art of Medicine is loved, there is also love of Humanity.

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1 SAGES NEWS VOLUME 10 FALL 2016 MESSAGE FROM THE DIRECTOR INSIDE THIS ISSUE: Dear SAGES Participants, Warmest greetings from the SAGES study! You are the lifeblood of our study and we are profoundly grateful for your involvement and support. We are tremendously excited to present the 10 th issue of the SAGES Newsletter. In these pages, you will read about recent publications and discoveries made possible by your generous participation in the SAGES study. You will also meet two of the study s researchers, Drs. Edward Marcantonio and Fah Vasunilashorn. And finally, we hope that you will join us in celebrating our latest SAGES study participation statistics; we are so thankful for your ongoing commitment. We also greatly appreciate your feedback about the SAGES study. Should you have any questions, comments, or concerns, please do not hesitate to reach us at (617) or sages@hsl.harvard.edu. We would love to hear from you. Sage (Salvia) MESSAGE FROM THE DIRECTOR INVESTIGATOR PROFILE: DR. EDWARD MARCANTONIO INVESTIGATOR PROFILE: DR. FAH VASUNILASHORN RECENT PUBLICATION HIGHLIGHTS ENROLLMENT UPDATE AND SAGES TEAM FUN FACTS With our deepest gratitude and best wishes, Eva M. Schmitt, PhD SAGES Study Director Sharon K. Inouye, MD, MPH SAGES Overall Principal Investigator Wherever the art of Medicine is loved, there is also love of Humanity. Hippocrates PAGE 1

2 PAGE 2 SAGES NEWS INVESTIGATOR PROFILE: EDWARD MARCANTONIO, MD, SM SAGES study lead investigator Dr. Edward Marcantonio wears many hats. In addition to advancing delirium research, Dr. Marcantonio is a Professor of Medicine at Harvard Medical School and the Section Chief for Research in the Division of General Medicine at the Beth Israel Deaconess Medical Center (BIDMC). Dr. Marcantonio was kind enough to sit down with us and tell us about his research, teaching, and clinical work, along with his motivation for studying delirium. What led you to a career in medicine? I have always been profoundly interested in math and science and eager to tangibly make a difference in people s lives. Medicine is a wonderful field because it allows me to help not only my immediate patients, but also a broader patient population though my research. Where did you receive your education and training? I attended Harvard Medical School and completed a residency in internal medicine at Brigham and Women s Hospital, followed by a clinical research fellowship at Harvard Medical School. I then received a Masters in Public Health and Clinical Epidemiology from Harvard Medical School, and pursued another fellowship in geriatric medicine at the Beth Israel Hospital, as it was then called. How did your career turn towards geriatric medicine and delirium research? During my clinical research fellowship at Harvard Medical School in the early 1990s, my mentor, cardiologist Dr. Lee Goldman, was conducting a study on the prevalence of heart attacks following major surgery. When he offered me the striking opportunity of studying any of the many common outcomes of surgery, I chose delirium (see Page 6 for a definition of delirium). At the time, delirium was on the cusp of receiving recognition from the research community. The tipping point came about when Dr. Sharon Inouye s Confusion Assessment Method (CAM), an instrument that allows non-psychiatrists to identify delirium, became widely known. I approached Dr. Inouye to add the CAM to Dr. Goldman s research study protocol, and my career in delirium research was born. (This career move benefited Dr. Goldman because, ironically, delirium was a much more common postoperative occurrence than heart attacks in his study and yielded much more interesting results than the heart attack angle). And ultimately, I ended up completing a geriatric fellowship at Beth Israel, (Continued on Page 3)

3 VOLUME 10 PAGE 3 (Continued from Page 2) where I deepened my knowledge of cognitive function and delirium. When did you begin to formally collaborate with Dr. Inouye? I began to formally collaborate with Dr. Inouye in Together, we designed the Program Project Grant which, when funded in 2010, formed the basis for the SAGES Study. What is your role in SAGES? I am the leader of Project 2 (see Page 7, Recent Publication Highlights), which is trying to identify differences in blood molecules between delirious vs. non-delirious individuals. Where do you see the SAGES study in another six years? I anticipate that we will continue recruiting patients at the BIDMC and following patients who had surgery between 2010 and 2013 to determine how cognitive changes immediately after surgery influence long-term cognitive functioning. What do you see as the greatest obstacle in advancing delirium research? We still do not fully understand what physiological changes within the brain correlate with the clinical phenomenon of delirium. We will need to further study brain waves and function and employ a host of techniques such as magnetic resonance imaging (MRI), transcranial magnetic stimulation (TMS), and electroencephalography (EEG). Furthermore, delirium researchers need to develop a better network so as to combine results from multiple different studies and obtain a better understanding of all facets of delirium. What is your favorite aspect of the SAGES Study? The SAGES participants may not know this but, in addition to advancing delirium research, the SAGES Study has launched the careers of over half a dozen remarkable young investigators who will make powerful contributions to the field in the years to come. Another wonderful aspect of SAGES is the field team, or the research staff who enroll and follow-up with you, the SAGES participants. I am continually impressed by not only their competence, but also their kindness and thoughtfulness. And finally, although I do not often interact with the SAGES participants directly, I am extremely grateful to you for your ongoing commitment and tremendous contributions to the study. We have been amazed by your dedication over the past three to six years, and your role is growing even more crucial. There are so many questions remaining that can be answered only by future follow-up visits, and I am really looking forward to our future collaborations. And finally, a bit about yourself outside of SAGES: what do you do for fun? I enjoy playing the piano and cello, walking on the beach, cross-country skiing, and lately visiting colleges with my wife and 18 year-old daughter.

4 PAGE 4 SAGES NEWS INVESTIGATOR PROFILE: FAH VASUNILASHORN, PHD What is your role in the SAGES study? I am a post-doctoral fellow at Harvard Medical School and the Beth Israel Deaconess Medical Center (BIDMC), where I work mainly with SAGES co-investigators Edward Marcantonio, MD, SM, and Towia Libermann, PhD. I analyze and write about the biomarkers that predict outcomes after surgery with the aim of explaining the basic mechanisms behind changes in thinking and functioning. It is a really interesting job! How did you first get involved in the study? I was initially part of a translational program on aging, where I connected with Dr. Marcantonio. What do you find most challenging about the SAG- ES study? It is hard to pinpoint the top few questions we can answer. There is so much that I want to know. What do you think is the biggest obstacle in advancing delirium research? It is challenging to study a broad range of people and a diverse population. The SAG- ES study will yield important results, but since it is based solely in Boston, all of our findings may not necessarily apply to older adults everywhere. What is your favorite part of your job? The best part of this job is working on research puzzles and asking interesting questions of experts in the field. I am also so impressed by your willingness to give so much of your time and to talk about your experiences in the hospital and beyond. The depth and quality of the information is truly groundbreaking! Another remarkable aspect of the SAGES study is that we are also looking at the biological hypotheses for delirium by collecting blood samples. Doing so allows us to identify the key proteins involved in cognitive outcomes after surgery. How did you become interested in geriatric research? Years ago, I volunteered at a hospital and was assigned to a geriatrics ward. Where did you work prior to SAGES? I have been in this field since graduate school. But before pursing my PhD, I began my research career as an undergraduate, conducting research in the basic sciences on mutations in muscle contraction and antibacterial agents. This laboratory research sparked my interest in how biological models inform our understanding of health in human populations. I have since shifted my focus to humans, after discovering my fascination with the fundamental biological processes of aging through a summer research (Continued on Page 5)

5 VOLUME 10 PAGE 5 (Continued from Page 4) internship in the laboratory of Epidemiology, Demography, and Biometry at the National Institute on Aging (NIA). After this eye-opening experience at the NIA, I decided to pursue a doctorate. Where did you go to graduate school, and what was your thesis? As a doctoral student in Gerontology at the University of Southern California (USC), I focused my research on understanding how living in a high infection environment with little access to modern medicine influences health. Since that time, my work has targeted inflammation and aging, along with the health effects of chronic stress. How would someone describe you? A friendly, generally happy person! What do you do outside of work? I m usually taking care of my son! He is eight months old, so looking after him takes up most of my time. As an outdoorsy person, I love going on hikes. I also enjoy playing volleyball and watching volleyball games something that I do quite frequently, as my husband coaches the men s volleyball team at Emmanuel College. What might someone be surprised to know about you? I am an only child, and I am not an East Coast native I actually hail from California! What is your favorite place? Los Angeles. That is where I grew up and where my parents and in-laws still live. Select members of the SAGES Team, from L to R: Jen Kettell, Maggie Vella, Katelyn Parisi, Dr. Sharon Inouye, Jacqui Nee, Dr. Eva Schmitt, Jackie Gallagher, and Dr. Edward Marcantonio.

6 PAGE 6 SAGES NEWS RECENT PUBLICATION HIGHLIGHTS We are so excited to share with you some of the recent publications from the SAGES Study. We will feature these publications in today s and future newsletters. Your contributions have made these important studies possible. We hope you take great pride in these major contributions to science and medicine. As you know, the SAGES Study focuses on thinking and memory before and after major surgery, as well as other surgical outcomes. The publications described here are concerned with delirium, an acute confusional state that can sometimes occur following surgery or hospitalization. Delirium, which occurred in about 1 in 5 of SAGES participants, is a condition that remains poorly understood and its long-term consequences remain uncertain. Delirium is not the same as dementia, which is a chronic, progressive confusional state, which has been extensively studied. One of the goals of SAGES is to help us better understand delirium so that prevention can be more effective and better treatments can be developed. Please note that all analyses in these publications are based on group data and averages; no individual person s data is ever examined separately. The types of measurements we take are for research purposes only, and are not the same as would be done at your doctor s office. It is not possible to make medical diagnoses or treatment decisions using information from SAGES. In addition, our Institutional Review Board requires that the data be used only for research purposes. Thus, our study policy is that individual data cannot be released. If you have concerns about your health, we encourage you to speak with your doctor or healthcare professional, who has access to your complete medical records and history. He or she can answer your questions, and discuss whether any evaluation is needed. Thank you again for your participation in this important work! Glossary of Key Terms: Cytokines (regulatory proteins of the immune system that are present in the blood); Inflammation (reaction of the body s immune system to perceived damage or insult); Biomarkers (indicators of disease); MRI (magnetic resonance imaging, a scan that produces crosssectional images of the brain). Novel risk markers and longterm outcomes of delirium: The Successful Aging after Elective Surgery (SAGES) study design and methods. J Am Med Dir Assoc. 2012; 13: 818e1-10. PMC Authors: Schmitt EM, Marcantonio ER, Alsop DC, Jones RN, Rogers SO, Fong TG, Metzger E, Inouye SK, and the SAGES Study Group. This paper describes the SAG- ES Study, viewed as a seminal undertaking to better understand the long-term outcomes of surgery and its association with delirium and cognitive functioning. The SAGES Study is an observational study following 560 persons over the age of 70 who underwent major scheduled surgery. All of the tests that you volunteered for including baseline neuropsychological and functional assessment prior to hospitalization, daily assessment during hospitalization, blood draws in the hospital and one month after discharge, and home-based interviews at the one, two, and six months after surgery for at least 36 months or more have provided us with very important data about longterm outcomes following surgery. (Continued on Page 7)

7 VOLUME 10 PAGE 7 (Continued from Page 6) SAGES consists of four subprojects: Project 1 looks at the role of delirium in long-term functional and cognitive decline; Project 2 tests your blood specimens in the laboratory to identify biomarkers for delirium and cognitive decline, such as cytokines, or regulatory proteins within the immune system; Project 3 examines your MRI scans and other neuroimaging data for markers that may be associated with delirium or cognitive decline; Project 4 looks at factors that can enhance resilience or the ability to withstand cognitive decline, such as level of education, occupation, physical and social lifestyle factors, and brain volume. Ultimately, these combined subprojects will help us to advance clinical understanding of the risk factors and outcomes of delirium and cognitive decline following surgery, helping us to prevent and treat these conditions in the long-term. Thus, your participation is making fundamental advances in this highly important area. Cytokines and postoperative decline in older patients undergoing major elective surgery. J Gerontol A Biol Sci Med Sci. 2015; 70: PMC Authors: Vasunilashorn SM, 1 Ngo L, 1 Inouye SK, Libermann TA, Jones RN, Alsop DC, Guess J, Jastrzebski S, McElhaney JE, Kuchel GA, 2 Marcantonio ER. 2 ( 1 these authors contributed equally as co-first authors; 2 these authors contributed equally as co-senior authors). This frontier paper was made possible by your blood samples. Your specimens allowed our researchers to delve into the pathophysiology of delirium, examining the relationship between delirium and certain regulatory proteins of the immune system known as cytokines. Cytokines had sparked the interest of our research team because the complex interplay between different types of these proteins is involved in modulating immune system inflammation which, in turn, has been linked to delirium. In order to determine the relationship between the activity of particular cytokines and the ebb and flow of delirium, we looked at your blood samples. As you may remember, we collected blood at four different timepoints: before surgery, shortly after surgery, two days after surgery, and 30 days after discharge. Because we wanted to compare blood cytokine levels in delirious vs. non-delirious patients, we also conducted a series of daily interviews with you to chart any changes in your functional abilities over time. Ultimately, the research team found that the levels of different cytokines varied across the timepoints and some correlated with delirium. For example, cytokine interleukin-2 (IL-2) is elevated prior to the onset of delirium, whereas interleukin-6 (IL-6) levels spike two days after surgery and fall at 30 days after discharge. Thus, the results suggest that IL-2 may be a risk marker for delirium, whereas IL -6 is an indicator that delirium has already occurred. If confirmed by future studies, these findings, based on the study data you have provided, could greatly advance patient treatment by identifying important risk markers and potential treatment targets for the future.

8 VOLUME 10 PAGE 8 Visit Month Progress Update Number of SAGES Participants Who Completed the Interview Thank you!!! Fun Facts and updates from the SAGES team The SAGES Team threw Dr. Sharon Inouye a surprise birthday party... Katelyn Parisi went canyon jumping while studying abroad in Switzerland as an undergraduate at Fairfield University. Newsletter Editorial Team: Penelope Reichenhall and Asha Albuquerque