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Recent Publications

COVID-19 and Older Adults

Kennedy M*, Helfand BK*I,  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 TT,. Wong AH, Taylor A, Davenport K, Teresi B, Fong TG*, and Inouye SK*.  Delirium in older patients with COVID-19 presenting to the emergency department.   In press (*These authors contributed equally to the manuscript).

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 http://www.clinicaltrials.gov 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

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.

 

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.


Delirium Severity

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.

Find instruments at https://hospitalelderlifeprogram.org/delirium-instruments

 

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.


Social Determinants of Delirium

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

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.


Functional Recovery after Surgery:

Racine AM, Fong TG, Gou Y, Travison TG, Tommet D, Erickson K, Jones RN, Dickerson BC, Metzger E, Marcantonio ER, Schmitt EM, Inouye SK. Clinical outcomes in older surgical patients with mild cognitive impairment. Alzheimers Dement. 2018; 14;590-600. PMC5938115.

Mild cognitive impairment (MCI) is a slow worsening of memory or thinking that only interferes slightly with functional ability. Older adults with MCI are increasingly undergoing surgery. MCI is associated with increased risk of delirium incidence and severity. Patients with delirium and MCI have a synergistically elevated risk of developing new difficulties in cognitively demanding tasks.

 

Pisani MA,1 Albuquerque A,1 Marcantonio ER, Jones RN, Gou RY, Fong TG, Schmitt EM, Tommet D, Isaza Aizpurua II, Alsop DC, Inouye SK,2 Travison TG.2 Association Between Hospital Readmission and Acute and Sustained Delays in Functional Recovery During 18 Months After Elective Surgery: The Successful Aging after Elective Surgery Study. J Am Geriatr Soc. 2017; 65:51-58. PMC5258816. (1these authors contributed equally as co-first authors; 2these authors contributed equally as co-senior authors).  

Because hospitalization as a result of any admitting diagnosis has been shown to contribute to a subsequent decline is health, we sought to determine the effects of rehospitalization on functional recovery after elective surgery. To gauge rehospitalization, we conducted interviews with a prospective cohort of elderly elective surgery patients  and their families over an 18 month period; to determine physical function, we employed the Instrumental Activities of Daily Living, Activities of Daily Living, the SF-12 Physical Component Summary, and a standardized functional composite. Our results indicate that readmissions may contribute to a delay in functional recovery, impacting all facets of physical function. These findings accord with a growing consensus that interventions aimed at preventing unanticipated readmissions or reducing the functional effects of readmission are of great benefit to older adults undergoing surgery.

 

Hshieh TT,1 Saczynski J,1 Gou RY, Marcantonio E, Jones RN, Schmitt E, Cooper Z, Ayres D, Wright J, Travison TG,2 Inouye SK.2 Trajectory of functional recovery after postoperative delirium in elective surgery. Ann Surg. 2017; 265(4):647-653.  PMC5292310 (1these authors contributed equally as co-first authors; 2these authors contributed equally as co-senior authors).  

In order to describe functional recovery after elective surgery and determine whether postoperative recovery trajectory differs between those who do and do not develop delirium, we employed a prospective observational study involving the SAGES cohort. Delirium incidence and severity were assessed during the hospital stay of elderly individuals undergoing major elective surgery; functional recovery was gauged by administration of the Activities of Daily Living and Instrumental Activities of Daily Living Scales and Phsycial Component Summary of the Short-Form 12 before surgery and at 1, 2, 6, 12, and 18 month postoperative intervals. Our findings indicate that delirium is significantly correlated with impairment to functional recovery, up to 18 months postoperative. Moreover, individuals at high risk for delirium may reap more functional benefit from elective surgery through  multifacted preoperative interventions and an individualized postoperative course of care.


Cognitive Performance and Delirium:

Daiello LA, Racine AM, Gou RY, Marcantonio ER, Xie Z, Kunze LJ, Vlassakov KV, Inouye SK*, Jones RN* for the SAGES Study Group. Postoperative delirium and postoperative cognitive dysfunction: overlap and divergence. Anesthesiology. 2019. Epub ahead of print. (*co-senior authors)

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.

 

Fong TG,* Hshieh TT,* Wong B, Tommet D, Jones RN, Schmitt EM, Puelle MR, Saczynski J, Marcantonio ER, Inouye SK. Neuropsychological profiles of an elderly cohort undergoing elective surgery and the relationship of cognitive performance with delirium. J Am Geriatr Soc. 2015; 63:977-82. PMC4497521 (*these authors contributed equally). 

We examined neuropsychological test performance in older adults in the SAGES study. We wanted to test if patients who developed delirium after surgery performed differently on neuropsychological tests prior to the surgery compared to patients who did not develop post-operative delirium. We found that patients who developed delirium had lower scores on tests in areas of complex attention, executive function, and verbal knowledge before surgery. Future studies will need to examine how cognitive performance may predispose individuals to developing delirium, and could help pave the way to greater understanding of the mechanisms of delirium. Future work may also consider how interventions such as training programs that boost “brain fitness” might strengthen attention and memory, preventing the post-operative cognitive decline that is frequently observed in older adults.


Cognitive Reserve and Delirium Risk

Saczynski JS,* Inouye SK,* Kosar C, Tommet D, Marcantonio ER, Fong T, Hshieh T, Vasunilashorn S, Metzger ED, Schmitt E, Alsop DC, Jones RN. Cognitive and brain reserve and the risk of postoperative delirium in older patients. Lancet Psychiatry. 2014; 1:437-443. PMC4307596 (*these authors contributed equally).

This is the first study to simultaneously examine multiple markers of cognitive and brain reserve as risk factors for the incidence of postoperative delirium. The results indicate that of eight markers of cognitive and brain reserve, only performance on a verbal intelligence test, the Wechsler Test of Adult Reading, was associated with the development of delirium. Our findings suggest that the reserve markers that are important for delirium may be different from those considered to be important for dementia. One important area for future research is to examine whether cognitive and brain reserve markers are associated with functional and cognitive recovery following delirium.


Non-pharmacological Delirium Interventions

Chen CC, Li HC, Liang J, Lai I, Purnomo J, Yang Y, Lin B, Huang J, Yang C, Tien Y, Chen C, Lin M, Huang G, Inouye SK. A Modified Hospital Elder Life Program Reduces Abdominal Surgery Patients' Delirium and Length of Hospital Stay: A Cluster-Randomized Trial. JAMA Surgery. 2017; 152:827-834. PMC5710459.

The purpose of this study was to determine whether a modified Hospital Elder Life Program (mHELP) could reduce incident delirium and length of stay in patients undergoing abdominal surgery. This cluster randomized controlled trial enrolled 377 older patients (>65 years old) who had undergone gastrectomy, pancreaticoduodenectomy, and colectomy in a 2,000-bed urban medical center in Taipei, Taiwan. The primary outcome was delirium incidence during hospitalization and the secondary outcome was hospital length of stay. The intervention (implemented by a mHELP nurse) consisted of the daily hospital-based mHELP comprising three protocols: orienting communication, oral and nutritional assistance, and early mobilization. Intervention-group participants received all three mHELP protocols postoperatively, in addition to usual care, as soon as they arrived on the inpatient ward and until hospital discharge. Our results show that for patients who received mHELP, the odds of delirium were reduced by 56% and the hospital length of stay was reduced by two days. These findings support using mHELP to advance postoperative care for older patients undergoing major abdominal surgery.

 

Hshieh TT, Yue J, Oh E, Puelle M, Dowal S, Travison T, Inouye SK. Effectiveness of multi-component non-pharmacologic delirium interventions: A Meta-analysis. JAMA Intern Med. 2015; 175: 512-520. PMC4388802. 

The purpose of this study was to evaluate available evidence on multicomponent nonpharmacological delirium interventions in reducing incident delirium and preventing poor outcomes associated with delirium. We identified 14 interventional studies that examined delirium incidence, falls, length of stay, rate of discharge to a long-term care institution (institutionalization), or change in functional or cognitive status. Overall, 11 studies demonstrated significant reductions in delirium incidence. Four randomized or matched trials reduced delirium incidence by 44%. The rate of falls decreased significantly among intervention patients in 4 studies; in 2 randomized or matched trials, the rate of falls was reduced by 64%. We conclude that multicomponent nonpharmacological delirium prevention interventions are effective in reducing delirium incidence and preventing falls, with a trend toward decreasing length of stay and avoiding institutionalization. Given the current focus on prevention of hospital-based complications and improved cost-effectiveness of care, this meta-analysis supports the use of these interventions to advance acute care for older persons.


Delirium Biomarkers

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.

 

Hshieh TT, Dai W, Cavallari M, Guttmann CRG, Meier DS, Schmitt EM, Dickerson BC, Press DZ, Marcantonio ER, Jones RN, Gou YR, Travison TG, Fong TG, Ngo L, Inouye SK,* Alsop DC*. Cerebral blood flow MRI in the nondemented elderly is not predictive of post-operative delirium but is correlated with cognitive performance. J Cereb Blood Flow Metab. 2017; 37: 1386-97. PMC in process. (*these authors contributed equally as co-senior authors).

Abnormalities in cerebral blood flow (CBF) can indicate cerebrovascular dysfunction as global and regional CBR aberrances have arisen during brain imaging of patients experiencing delirium. We probed the possible correlation between Arterial Spin Labeling (ASL) MRI measures of preoperative CBF with postoperative delirium incidence and severity, along with the cross-sectional association of CBF with patients' baseline performance on neuropsychological tests and their composite general cognitive performance (GCP). Our results indicate that ASL is a feasible instrument for examining association between CBF and age-related cognitive performance. Moreover, ASL CBF measures in regions associated with preclinical Alzheimer's Disease correlated with cognition but did not indicate a pathophysiological risk for delirium.

 

Vasunilashorn S, Ngo L, Kosar CM, Fong TG, Jones RN, Inouye SK,* Marcantonio ER.* Does Apolipoprotein E Genotype Increase Risk of Postoperative Delirium? Am J Geriatr Psychiatry. 2015; 23:1029-37. PMC4591079 (*these authors contributed equally as co-senior authors).

Apolipoprotein ε4 (ApoE) is a known risk factor for Alzheimer’s Disease, and we predicted that the gene might also be a risk factor for delirium. However, our results show that ApoE does not affect risk for delirium, which suggest that delirium is not merely a sign of early Alzheimer’s, but holds its own clinical significance.

 

Cavallari M,1 Hshieh TT,1 Guttmann CG, Ngo LH, Meier DS, Schmitt EM, Marcantonio ER, Jones RN, Kosar CM, Fong TG, Press DZ, Inouye SK,2 Alsop DC,2 SAGES Study Group. Brain atrophy and white matter hyperintensities are not significantly associated with incidence and severity of postoperative delirium in older persons without dementia. Neurobiol Aging. 2015; 36:2122-2129. PMC4433616 (1these authors contributed equally as co-first authors; 2these authors contributed equally as co-senior authors). 

This study used state-of-the-art magnetic resonance imaging (MRI) to examine a cohort of patients without dementia undergoing elective surgery. There were no significant differences in brain volume, hippocampal volume, or white matter damage between patients with and without delirium. Future studies may consider whether other measures of brain pathology may be useful for predicting delirium.


Delirium Severity Measurement

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.

Find instruments at https://hospitalelderlifeprogram.org/delirium-instruments

 

Inouye SK, Kosar CM, Tommet D, Schmitt EM, Puelle MR, Saczynski JS, Marcantonio ER, Jones RN. The CAM-S: Development and Validation of a New Scoring System for Delirium Severity in 2 Cohorts. Ann Intern Med. 2014; 160: 526-533. PMC4038434.

Dr. Inouye and colleagues developed the CAM-S, a delirium severity scoring system that has shown strong correlation with clinical outcomes in hospitalized older patients, including length of stay, functional decline, and death. The new scoring system, CAM-S, is based on the Confusion Assessment Method (CAM) and standardizes the measurement of delirium severity for both clinical and research uses. This measure holds great promise to improve understanding of the effects of delirium on clinical care, prognosis, pathophysiology, and response to treatment.