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Recent Publications

For complete list of publications, please see Dr. Inouye's page on the Harvard Catalyst.
COVID-19 and Older Adults
Mak W, Prempeh A, Schmitt E, Fong T, Marcantonio ER, Inouye SK, Boockvar K. Delirium after COVID-19 Vaccination in Nursing Home Residents: A Case Series. J Am Geriatr Soc. 2022; 70 (6): 1648-1651.
In this study of 40 participants at a 514-bed nursing home, during 1-2 day initiatives to provide COVID-19 vaccinations to residents, three participants had delirium the day after the COVID-19 vaccination and one participant had subsyndromal delirium. None had competing cases of delirium, and all delirium resolved. This study relayed the importance of monitoring for delirium in older adults after vaccination, but overall emphasized that the risk-benefit ratio strongly supports vaccination.
Fong TG, Chan NY, Dillon ST, Zhou W, Tripp B, Ngo LH, Otu HH, Inouye SK, Vasunilashorn SM, Cooper Z, Xie Z, Marcantonio ER, Libermann TA. Identification of Plasma Proteome Signatures Associated With Surgery Using SOMAscan. Ann Surg. 2021 Apr 1;273(4):732-742. doi: 10.1097/SLA.0000000000003283.
In this manuscript, the ability of SOMAscan technology to identify proteins differentially expressed before and after surgery in older adults was evaluated. Systems biology analyses demonstrated that inflammatory proteins and biological functions associated with the inflammatory response and immune cell regulation demonstrated the greatest changes after surgery. SOMAscan can identify novel and clinically relevant surgery-induced protein changes. Ultimately, proteomics may provide insights about pathways by which surgical stress contributes to postoperative outcomes.
Kennedy M, Helfand BKI, Gou RY, Gartaganis SL, Webb M, Moccia JM, Bruursema SN, Dokic B, McCulloch B, Ring H, Margolin JD, Zhang E, Anderson R, Babine RL, Hshieh T, Wong AH, Taylor RA, Davenport K, Teresi B, Fong TG, Inouye SK. Delirium in Older Patients With COVID-19 Presenting to the Emergency Department. JAMA Netw Open. 2020 Nov 2;3(11):e2029540. doi: 10.1001/jamanetworkopen.2020.29540.
In this cohort study of 817 older ED patients with COVID-19, 226 (28%) had delirium at presentation, the sixth most common of all presenting symptoms and signs. Among delirious patients, 16% presented with delirium as a primary symptom and 37% had no typical COVID-19 symptoms or signs, such as cough or fever. These findings indicate that older adults with COVID-19 commonly present to the ED with delirium and delirium should be considered an important presenting symptom of COVID-19.
Helfand BKI, Webb M, Gartaganis SL, Fuller L, Kwon C, Inouye SK. The Exclusion of Older Persons From Vaccine and Treatment Trials for Coronavirus Disease 2019—Missing the Target. JAMA Intern Med. 2020. Epub Ahead of Print. PMC in process.
We reviewed all COVID-19 treatment and vaccine trials on to evaluate their risk for exclusion of older adults (≥65 years). Our findings indicate that older adults are likely to be excluded from more than 50% of COVID-19 clinical trials and 100% of vaccine trials. Such exclusion will limit the ability to evaluate the efficacy, dosage, and adverse effects of the intended treatments.

Delirium Biomarkers
Dillon ST, Out HH, Ngo LH, Fong TG, Vasunilashorn SM, Xie Z, Kunze LJ, Vlassakov KV, Abdeen A, Lange JK, Earp BE, Cooper ZR, Schmitt E, Arnold SE, Hshieh T, Jones RN, Inouye SK, Marcantonio ER, Libermann TA. Patterns and persistence of perioperative plasma and CSF neuroinflammatory protein biomarkers after elective orthopedic surgery using SOMAscan. Anesth Analg. 2022; In Press.
The Role of Inflammation after Surgery for Elders (RISE) study includes participants undergoing elective hip and knee replacement surgery with spinal anesthesia. Systems biology analysis identified biological pathways enriched among the surgery associated differentially expressed proteins in plasma and CSF. A comparison between preoperative and postoperative day 1 (POD1) plasma protein levels located 343 proteins with postsurgical changes. Comparing plasma and CSF between preoperative and post operative 1-month (PO1MO) identified 67 proteins in plasma and 79 proteins in CSF with altered levels. Parallel plasma protein and CSF changes between POD1 and PO1MO respectively suggests 15 potential biomarkers for longer-term neuroinflammation.
Fong TG*, Vasunilashorn SM*, Ngo L, Libermann TA, Dillon ST, Schmitt EM, Pascual-Leone A, Arnold SE, Jones RN, Marcantonio ER*, Inouye SK* for the SAGES Study Group. Association of Plasma Neurofilament Light with Postoperative Delirium. Ann Neurol. 2020. Epub Ahead of Print. PMC in process. (*These authors contributed equally to the manuscript).
Neurofilament light (NfL) is protein that provides structural support for myelinated axons and has been found to be elevated in blood in multiple conditions including stroke, traumatic brain injury,  multiple sclerosis, Alzehiemer’s disease, progressive supranuclear palsy, and frontotemporal dementia, and delirium.  In this study we found that patients with the highest levels of NfL, both prior to surgery or 2 days after surgery,  were more likely to develop delirium.  Elevated NfL  a month after surgery  was associated with delirium and greater cognitive decline.  These findings  suggest NfL may be useful as a predictive biomarker for delirium risk and long-term cognitive decline, and once confirmed would  provide pathophysiological evidence for neuroaxonal injury following delirium.
Katsumi Y, Racine AM, Torrado-Carvajal A, Loggia ML, Hooker JM, Greve DN, Hightower BG, Catana C, Cavallari M, Arnold SE, Fong TG, Vasunilashorn SM, Marcantonio ER, Schmitt EM, Xu G, Libermann TA, Barrett LF, Inouye SK*, Dickerson BC*, Touroutoglou A*. Collins J* for the RISE Study Group. The Role of Inflammation after Surgery for Elders (RISE) study: Examination of [11C]PBR28 binding and exploration of its link to post-operative delirium. NeuroImage Clin. 2020. In Press. (*co-senior authors).
In the present study, [(11)C]PBR28 positron emission tomography, cerebrospinal fluid (CSF), and blood plasma biomarkers of inflammation were assessed pre-operatively and 1-month post-operatively in a cohort of patients undergoing major orthopedic surgery under spinal anesthesia. Delirium incidence and severity were evaluated daily during hospitalization. Whole-brain voxel-wise and regions-of-interest analyses were performed to determine the magnitude and spatial extent of changes in [(11)C]PBR28 uptake following surgery. No significant relationship was identified between post-operative delirium and [(11)C]PBR28 binding.
Racine AM, Touroutoglou A, Abrantes T, Wong B, Fong TG, Cavallari M, Travison TG, Gou Y, Marcantonio ER, Alsop DC, Jones RN, Inouye SK*, Dickerson BC*. Older patients with Alzheimer’s-related cortical atrophy who develop post-operative delirium may be at increased risk of long-term cognitive decline after surgery. J Alzheimers Dis. 2020; 75:187-199. PMC7304614. (*co-senior authors).
The Successful Aging after Elective Surgery cohort includes older adults (≥70 years) without dementia who underwent elective surgery. Patients (n=140) underwent preoperative magnetic resonance imaging and had≥6 months cognitive follow-up. Cortical thickness was measured in 'AD-Signature' regions. Patients with the greatest baseline AD-related cortical atrophy who develop delirium after elective surgery appear to experience the greatest long-term cognitive decline. Thus, atrophy suggestive of preclinical AD and the development of delirium may be high-risk indicators for long-term cognitive decline following surgery.
Fong TG, Chan NY, Dillon ST, Zhou W, Tripp B, Ngo LH, Otu HH, Inouye SK, Vasunilashorn SM, Cooper Z, Xie Z, Marcantonio ER*, Libermann TA*. Identification of plasma proteome signatures associated with surgery using SOMAscan. Annals of Surgery, 2019. Epub ahead of print. PMC in process. (*co-senior).
In this manuscript, the ability of SOMAscan technology to identify proteins differentially expressed before and after surgery in older adults was evaluated. Systems biology analyses demonstrated that inflammatory proteins and biological functions associated with the inflammatory response and immune cell regulation demonstrated the greatest changes after surgery. SOMAscan can identify novel and clinically relevant surgery-induced protein changes. Ultimately, proteomics may provide insights about pathways by which surgical stress contributes to postoperative outcomes.

Delirium Severity
Vasunilashorn SM, Fong TG, Helfand BK, Hshieh TT, Marcantonio ER, Metzger ED, Schmitt EM, Tabloski PA, Travison TG, Gou Y, Jones RN, Inouye SK. Psychometric Properties of a Delirium Severity Score for Older Adults and Association with Hospital and Posthospital Outcomes. JAMA Netw Open. 2022; 5(3):e226129. doi: 10.1001/jamanetworkopen.2022.6129. PMID: 35357447.
In this validation study of 352 participants, we found that patients in the highest delirium severity score SF group (scores 6-9) had a longer length of stay, greater in-hospital costs, greater cumulative health care costs, and increased mortality at 1 year compared with patients in the lowest delirium severity score SF group.
Schulman-Green D*, Hshieh T*, Adamis D, Avidan MS, Blazer DG, Fick DM, Oh E, Morandi A, Price C, Verghese J, Schmitt EM, Jones RN**, Inouye SK**. Domains of Delirium Severity in Alzheimer’s Disease and Related Dementias. J Am Geriatr Soc. 2021 Dec 24; doi: 10.1111/jgs.17624. (*co-first authors; **co-senior authors).
We defined content domains for a new delirium severity instrument for use in individuals with mild to moderate ADRD, the DEL-S-AD. Through engaging a new expert panel to discuss issues of measurement in delirium and dementia, we obtained a list of endorsed content domains: Cognitive, Level of Consciousness, Inattention, Psychiatric-Behavioral, Emotional Dysregulation, Psychomotor Features, and Functional.
Hshieh TT, Fong TG, Schmitt EM, Marcantonio ER, Xu G, Gou YR, Travison TG, Metzger ED, Jones RN, Inouye SK, for the BASIL Study Group. Does Alzheimer’s Disease and Related Dementias Modify Delirium Severity and Hospital Outcomes? J Am Geriatr Soc. 2020. 68:1722-1730. PMC in process.
In this paper, we examined the relationship between delirium severity and hospital outcomes in patients with and without Alzheimer’s disease and related dementias (ADRD).  Severe delirium was associated with increased risk for poor clinical outcomes in patients both with and without ADRD. In both groups, severe delirium increased risk of nursing home placement. However, in patients with ADRD, delirium was more severe and associated with a trend toward increased mortality at 1 month.
Schulman-Green D, Schmitt EM, Fong TG, Vasunilashorn SM, Gallagher J, Marcantonio ER, Brown CH, Clark D, Flaherty JH, Gleason A, Gordon S, Kolanowski AM, Neufeld KJ, O’Connor M, Pisani MA, Robinson TN, Verghese J, Wald HL, Jones RN*, Inouye SK*. Use of an expert panel to identify domains and indicators of delirium severity. Qual Life Res. 2019; 28:2565-2578. (*co-senior authors). PMC6858057.
We used an established, multi-stage instrument development process during which twelve national delirium experts and four expert members of the core research group discussed best approaches to measure delirium severity and identified related content domains. Experts recommended that the construct of delirium severity should reflect both the phenomena and the impact of delirium to create an accurate, patient-centered instrument useful to interdisciplinary clinicians and family caregivers. We believe this work represents the first application of instrument development science to delirium. Our content domain framework provides a foundation for development of delirium severity instruments that can help improve care and quality of life for patients with delirium.
Jones RN, Cizginer S, Pavlech L, Albuquerque A, Daiello LA, Dharmarajan K, Gleason LJ, Helfand B, Massimo L, Oh ES, Okereke OI, Tabloski P, Rabin L, Yue J, Marcantonio ER, Fong TG, Hshieh TT, Metzger E, Erickson K, Schmitt E, Inouye SK for the BASIL Study Group. Assessment of instruments for measurement of delirium severity: a systematic review. JAMA Intern Med. 2019; 179:231–239. PMC6382582.
Measurement of delirium severity has been recognized as highly important for tracking prognosis, monitoring response to treatment, and estimating burden of care for patients both during and after hospitalization. Rather than simply rating delirium as present or absent, the ability to quantify its severity would enable development and monitoring of more effective treatment approaches for the condition. The 6 delirium severity instruments identified in this systematic review may enable accurate measurement of delirium severity to improve clinical care for patients with this condition. This work may stimulate increased usage and head-to-head comparison of these instruments.

Social Determinants of Delirium
Arias F, Alegria M, Kind AJ, Jones RN, Travison TG, Marcantonio ER, Schmitt EM, Fong TG, Inouye SK. A Framework of Social Determinants of Health for Delirium Tailored to Older Adults. J Am Geriatr Soc. 2022 Jan; 70(1):235-242. doi: 10.1111/jgs.17465. PMC8742772.
We must adapt our understanding of social determinants of health (SDOH) to ensure relevance for older adults in consideration of delirium. Our novel framework aims to comprehensively capture the social circumstances, environmental characteristics, and life course factors that may protect against or precipitate delirium in older adults.
Arias F, Chen F, Fong TG, Shiff H, Alegria M, Marcantonio ER, Gou Y, Jones RN, Travison TG, Schmitt EM, Kind AJH*, Inouye SK*. Neighborhood-Level Social Disadvantage and Risk of Delirium Following Major Surgery. J Am Geriatr Soc. 2020. Epub Ahead of Print. PMC in process. (*co-senior authors).
Area deprivation index, a ranking of neighborhoods by socioeconomic status which considers  income, education, employment, and housing quality, was used to determine whether social disadvantage was associated with Delirium.  We found that residing in the most disadvantaged neighborhoods (ADI > 44) was associated with a higher risk of incident delirium and more severe delirium.  This association followed an exposure-response relationship.

Interface between Delirium and Dementia
Fong TG and Inouye SK. The Inter-relationship between delirium and dementia and the importance of delirium prevention. Nat Rev Neurol. 2022; In Press.
Through reviewing biomarkers that are shared between delirium and dementia, we explore mechanisms they have in common. Overall, the importance of delirium recognition and prevention in people with dementia is emphasized.
Vasunilashorn SM, Ngo LH, Inouye SK, Fong TG, Jones RN, Dillon ST, Libermann TA, O’Connor M, Arnold SE, Xie Z, Marcantonio ER. Apolipoprotein E genotype and the association between C-reactive protein and postoperative delirium: Importance of gene-protein interactions. Alzheimers Dement. 2020; 16:572-580. PMC7086383
The ApoE4 gene has been shown to greatly increase the odds that an individual will develop Alzheimer's disease.   In this paper we explored the relationship between CRP and delirium incidence, severity, and duration. Among epsilon4 carriers, there was a strong relationship between high CRP and delirium incidence but not among non-epsilon4 carriers.  These findings raise the possibility that APOE epsilon4 carrier status may modify the relationship between postoperative day 2 CRP levels and postoperative delirium.
Fong TG*, Racine AM*, Fick DM, Tabloski P, Gou Y, Schmitt EM, Hshieh TT, Metzger E, Bertrand SE, Marcantonio ER, Jones RN, Inouye SK. The Caregiver Burden of Delirium in Older Adults with Alzheimer Disease and Related Disorders. J Am Geriatr Soc. 2019; 67:2587-2592. PMC6898752. (*These authors contributed equally to this work)
Delirium can be burdensome for both patient and caregiver, owing to the subjective distress (i.e., fear, anxiety, suffering) associated with the experiential, emotional, and situational aspects of delirium.  We found that distress associated with delirium affects caregivers of patients with or without ADRD to the same extent, suggesting that experience as a caregiver of a person with dementia does not help prepare for coping with providing care to a person with delirium. Burden should be assessed in all caregivers of and patients with delirium. As with ADRD, caregiver and peer support programs, case management, counseling, education and long-term multicomponent programs should be explored as potential approaches to decrease caregiver distress in delirium.

Recovery and Costs after Surgery:
Gou RY, Hshieh TT, Marcantonio ER, et al. One-Year Medicare Costs Associated With Delirium in Older Patients Undergoing Major Elective Surgery. JAMA Surg. 2021;156(5):430–442. doi:10.1001/jamasurg.2020.7260
At the 1-year follow up post-major elective surgery, participants who had developed delirium accumulated an adjusted mean of 44,291 more than those without delirium. Additionally, the mean adjusted head care costs increased directly with delirium severity. Extrapolating nationally, health care costs attributable to post-operative delirium are >$33 billion per year.

Cognitive Performance and Delirium:
Daiello LA, Racine AM, Yun Gou R, Marcantonio ER, Xie Z, Kunze LJ, Vlassakov KV, Inouye SK, Jones RN, Alsop D, Travison T, Arnold S, Cooper Z, Dickerson B, Fong T, Metzger E, Pascual-Leone A, Schmitt EM, Shafi M, Cavallari M, Dai W, Dillon ST, McElhaney J, Guttmann C, Hshieh T, Kuchel G, Libermann T, Ngo L, Press D, Saczynski J, Vasunilashorn S, O'Connor M, Kimchi E, Strauss J, Wong B, Belkin M, Ayres D, Callery M, Pomposelli F, Wright J, Schermerhorn M, Abrantes T, Albuquerque A, Bertrand S, Brown A, Callahan A, D'Aquila M, Dowal S, Fox M, Gallagher J, Anna Gersten R, Hodara A, Helfand B, Inloes J, Kettell J, Kuczmarska A, Nee J, Nemeth E, Ochsner L, Palihnich K, Parisi K, Puelle M, Rastegar S, Vella M, Xu G, Bryan M, Guess J, Enghorn D, Gross A, Gou Y, Habtemariam D, Isaza I, Kosar C, Rockett C, Tommet D, Gruen T, Ross M, Tasker K, Gee J, Kolanowski A, Pisani M, de Rooij S, Rogers S, Studenski S, Stern Y, Whittemore A, Gottlieb G, Orav J, Sperling R; SAGES Study Group*. Postoperative Delirium and Postoperative Cognitive Dysfunction: Overlap and Divergence. Anesthesiology. 2019 Sep;131(3):477-491. doi: 10.1097/ALN.0000000000002729.
Postoperative delirium and postoperative cognitive dysfunction share risk factors and may co-occur, but their relationship is not well established. The primary goals of this study were to describe the prevalence of postoperative cognitive dysfunction and to investigate its association with in-hospital delirium. Delirium significantly increased the risk of postoperative cognitive dysfunction in the first postoperative month; this relationship did not hold in longer-term follow-up. At each evaluation, postoperative cognitive dysfunction was more common among patients without delirium. Postoperative delirium and postoperative cognitive dysfunction may be distinct manifestations of perioperative neurocognitive deficits.

Hospital Elder Life Program on Delirium
Wang YY, Yue JR, Xie DM, Carter P, Li QL, Gartaganis SL, Chen J, Inouye SK. Effect of theTailored, Family-Involved Hospital Elder Life Program on Postoperative Delirium and Function in Older Adults: A Randomized Clinical Trial. JAMA Intern Med. 2020 Jan 1;180(1):17-25. doi: 10.1001/jamainternmed.2019.4446.
The Hospital Elder Life Program interventions were conducted by family members conducted in West China, with the results of reduced post-operative delirium, shorter length of stay (by 4 days), and less decline in cognitive and physical function among the HELP group. Overall, t-HELP, with family involvement at its core, is effective.
Lorgunpai SJ, Finke B, Burrows I, Brown CJ, Rubin FH, Wierman HR, Heisey SJ, Gartaganis S, Ling SM, Press M, Inouye SK. Mobility Action Group: Using Quality Improvement Methods to Create a Culture of Hospital Mobility. J Am Geriatr Soc. 2020 Oct;68(10):2373-2381. doi: 10.1111/jgs.16699. Epub 2020 Aug 5.
In a study involving 42 hospitals of varying sizes across the USA in the attempt to implement mobility programs with the aim to meet mobility goals, we found that 76% of sites had success in implementing mobility programs. Furthermore, we saw an increase in the proportion of patients who received 3+ walks per day and a decrease in the proportion of patients who were placed on bed/chair alarm.

Developing Delirium Instruments
Racine AM, D'Aquila M, Schmitt EM, Gallagher J, Marcantonio ER, Jones RN, Inouye SK, Schulman-Green D; BASIL Study Group. Delirium Burden in Patients and Family Caregivers: Development and Testing of New Instruments. Gerontologist. 2019 Sep 17;59(5):e393-e402. doi: 10.1093/geront/gny041.
To address the limited existing tools to assess the unique emotional distress caused by delirium, we developed separate patient and family caregiver delirium burden instruments. In this study that tests these instruments, the Patient DEL-B-P was 5.1 points higher and the Family Caregiver DEL-B-C was 5.8 points higher for patients who developed delirium compared to those who did not. Furthermore, there was a significant correlation of Delirium Burden reflected by DEL-B with delirium severity by CAM-S score.