Abstract
Background:
The Successful Aging after Elective Surgery (SAGES) II study was designed to increase knowledge of the pathophysiology and linkages between delirium and dementia. We examine novel biomarkers potentially associated with delirium, including inflammation, Alzheimer’s disease (AD) pathology and neurodegeneration, neuroimaging markers, and neurophysiologic markers. The goal of this paper is to describe the study design and methods for the SAGES II study.
Methods:
The SAGES II study is a 5-year prospective observational study of 400–420 community dwelling persons, aged 65 years and older, assessed prior to scheduled surgery and followed daily throughout hospitalization to observe for development of delirium and other clinical outcomes.
Delirium is measured with the Confusion Assessment Method (CAM), long form, after cognitive testing. Cognitive function is measured with a detailed neuropsychologic test battery, summarized as a weighted composite, the General Cognitive Performance (GCP) score. Other key measures include magnetic resonance imaging (MRI), transcranial magnetic stimulation (TMS)/electroencephalography (EEG), and Amyloid positron emission tomography (PET) imaging. We describe the eligibility criteria, enrollment flow, timing of assessments, and variables collected at baseline and during repeated assessments at 1, 2, 6, 12, and 18 months.
Results:
This study describes the hospital and surgery-related variables, delirium, long-term cognitive decline, clinical outcomes, and novel biomarkers. In inter-rater reliability assessments, the CAM ratings (weighted kappa = 0.91, 95% confidence interval, CI = 0.74–1.0) in 50 paired assessments and GCP ratings (weighted kappa = 0.99, 95% CI 0.94–1.0) in 25 paired assessments. We describe procedures for data quality assurance and Covid-19 adaptations.
Conclusions:
This complex study presents an innovative effort to advance our understanding of the inter-relationship between delirium and dementia via novel biomarkers, collected in the context of major surgery in older adults. Strengths include the integration of MRI, TMS/EEG, PET modalities, and high-quality longitudinal data.
Keywords: biomarkers, cognitive decline, cognitive impairment, delirium, dementia, long-term cognitive decline
BACKGROUND
Delirium is a clinical syndrome characterized by inattention and disturbance in cognition that develops acutely with a fluctuating course.1 Delirium is a common, serious, and often fatal disorder associated with increased risk of functional decline, nursing home admission, prolonged length of hospital stay, and cognitive decline. It affects up to 60% of hospitalized seniors with costs exceeding $204 billion per year (2021 U.S. dollars).2–4 The adjusted cumulative healthcare costs due to severe delirium in post-operative patients in the U.S. are estimated at $56,474 (95% CI $40,927–$77,440) per patient over one year.5 As a preventable condition in 30%–50% of cases,2–4 delirium holds substantial public health relevance as a target for interventions to prevent its associated burden of downstream complications and costs.
The development of delirium has long been considered a “stress test,” a warning sign of depleted brain health and resilience in older people.6 The occurrence of an episode of delirium might signal underlying vulnerability of the brain with decreased cognitive reserve. Delirium may reflect a decompensated cognitive state under stress conditions, and its presence implies diminished neurocognitive resilience. In some cases, delirium may also serve to bring previously unrecognized cognitive impairment to medical attention.7,8 Delirium is an independent risk factor for long-term cognitive decline and dementia; in a literature review, delirium was associated with odds ratios of 2.4–8.8 for subsequent dementia.9 In a recent systematic review examining the relationship between delirium and cognitive decline, all 24 studies demonstrated an association.10 It is unknown whether delirium exacerbates the impact of noxious insults or precipitating factors, such as surgery, anesthesia, or severe infections, on the vulnerable brain. There is mounting evidence that delirium reflects pathologic phenomena that can lead to neuronal loss associated with cognitive impairment or dementia.11 Delirium and dementia have a reciprocal inter-relationship: in addition to delirium increasing risk of subsequent dementia, the presence of underlying dementia is one of the strongest risk factors for development of delirium.
We previously studied a cohort of >560 older surgical patients in the Successful Aging after Elective Surgery (SAGES I) Program Project Grant (P01AG031720),12,13 and found that delirium was followed by an accelerated trajectory of long-term cognitive decline.14 Important risk markers for delirium were elucidated, related to inflammation (Interleukin-6, C-Reactive Protein and Chitinase 3 Like Protein 1),15,16 structural dysconnectivity on MRI,17 and impairment in global cognitive performance.18 In an effort to validate knowledge of the interrelationship of delirium and dementia, including the pathophysiology of delirium and its potential linkage to dementia, we proposed the SAGES II study to examine novel biomarkers potentially associated with delirium, including new biomarkers of inflammation, Alzheimer’s disease (AD) pathology and neurodegeneration, neuroimaging markers, and neurophysiologic markers as well as a broad proteome survey. The goal of this paper is to describe the study design and methods for the novel SAGES II study. We acknowledge that there are many recent studies examining biomarkers for delirium and postoperative cognitive decline.19–23 The major advantage of the SAGES study is the large sample size, long follow-up with serial neuropsychologic testing and functional assessments, and the multicomponent nature of risk factors and biomarkers being examined.
CONCEPTUAL FRAMEWORK
A unifying conceptual framework for the study appears in Figure S1. The interface between delirium and dementia is complex, and a unified investigation of key potential pathophysiologic pathways may enhance our understanding of these relationships. Thus, this study includes four major pathophysiologic probes: (1) Alzheimer’s pathology derived from cerebrospinal fluid (CSF); (2) Alzheimer’s pathology derived from neuroimaging; (3) evidence of inflammation from CSF and plasma; and (4) brain plasticity and connectivity by electrophysiology. Each approach will examine brain vulnerability, and its contribution to delirium and complicated delirium (defined as delirium associated with subsequent long-term cognitive decline).
METHODS
Overview
SAGES II is a 5-year prospective observational study of 400–420 community dwelling persons, aged 65 years and older, assessed prior to scheduled surgery and followed daily throughout hospitalization for development of delirium and other clinical outcomes. Baseline assessments are conducted in participants’ homes, daily interviews while hospitalized, and follow-up interviews after discharge at 1, 2, 6, 12, and 18 months. Standardized assessments include demographic, cognitive, clinical, physical function, frailty, and emotional health measures. Blood is collected at four time points and CSF is collected at spinal anesthesia induction. Patients may volunteer for additional sub-studies, including magnetic resonance imaging (MRI), transcranial magnetic stimulation (TMS)/electroencephalography (EEG), and Amyloid positron emission tomography (PET) imaging.
Eligibility
Eligible surgery types and detailed inclusion/exclusion criteria are described in Table 1. Participating Harvard-affiliated enrollment sites include Beth Israel Deaconess Medical Center (BIDMC), Brigham and Women’s Hospital (BWH), and Brigham and Women’s Faulkner Hospital (BWFH). Cognitive function is screened at baseline: patients with active delirium or severe dementia are excluded. Patients with Montreal Cognitive Assessment (MoCA) score <20 are adjudicated for eligibility; however, patients with mild cognitive impairment (MCI) remain eligible, because we plan to examine the impact of delirium in this high-risk group. Patients who could not correctly respond to a capacity questionnaire are excluded. In cases where capacity is uncertain, the study director and study physician review and make eligibility determination. Written informed consent for study participation is obtained according to procedures approved by the institutional review board of BIDMC, the IRB of record; with reliance agreements from BWH/BWFH and HSL, the study coordinating center, all located in Boston, Massachusetts.
TABLE 1.
SAGES II recruitment
SAGES II | N = 400–420 (projected) |
---|---|
Inclusion criteria | • English speaking, able to communicate verbally • Scheduled to undergo major surgery at one of three Harvard-affiliated hospitals • Spinal or general anesthesia • Age 65 years and older • Mild cognitive impairment can participate • Eligible surgical procedures (same as SAGES I): total hip or knee replacement, lumbar, cervical or sacral laminectomy, lower extremity arterial bypass surgery, open abdominal aortic aneurysm repair, open or laparoscopic colectomy • Additional surgeries (SAGES II only): popliteal, GI resections (colectomy, bowel, mass, hepatectomy, gastrectomy, Rouex-en-Y), lumbar fusion, nephrectomy, prostatectomy, cystectomy |
Exclusion criteria a | |
Hard exclusions | • Delirious on admission, prior hospitalization within 3 months, severe dementia, legal blindness, severe deafness, terminal condition (<3 month survival), history of alcohol abuse or withdrawal • Lacks capacity to consent |
Soft exclusions (require adjudication) | • Diagnosis of moderate dementia (MoCA <20) • Active schizophrenia or psychosis • Metastatic solid organ cancer, leukemia, lymphoma (due to limited survival) • Active chemotherapy or hemodialysis (due to burden of participation) |
Substudy: Neuroimaging (MRI)b and Neurophysiology (TMS/EEG)c | MRI: n = 100–110 (projected); TMS/EEG: n = 90–95 (projected) |
Inclusions | Same as SAGES II |
Exclusions 19,24 | Hard exclusions: • History of prior neurosurgery • History of seizures or diagnosis of epilepsy (exception: single seizure of benign etiology, for example, febrile seizure) • Metal implants or devices such as a cardiac pacemaker or intracardiac lines, medication pump, any intracranial neurostimulator, external fixation devices, or bone growth stimulators • Any shrapnel or metal fragments anywhere in the body |
Soft exclusions: adjudicated by research team • Gastrointestinal monitoring device or interventional procedure within past 30 days • Implanted valves, stents, devices, prosthesis (e.g., metallic heart valve, aneurysm clips, cochlear implant, ventricular peritoneal shunt) • Metal injury to the eye or other body part |
|
Substudy: Amyloid-PET | n = 40–50 (projected) |
Inclusions | Same as SAGES II |
Exclusions | Prior scan with radioactive agents either for clinical or research purposes within 12 months, such that total research-related radiation dose exceeds limits set forth in the US Code of Federal Regulations (CFR) 21, Section 361.1 |
Exclusions: Primary reason for these criteria was to limit study burden for participants and to exclude patients with very limited life expectancy (i.e., <3 month survival).
Neuroimaging (MRI) in SAGES II includes additional imaging sequences different from SAGES I, specifically functional MRI and advanced multishell, multiband diffusion imaging.
TMS-only substudy has no additional exclusions.
Substudies: Neuroimaging, TMS/EEG, and amyloid PET
A subgroup of the SAGES II cohort, meeting additional exclusion criteria (Table 1), is offered MRI in 3-Tesla at baseline (projected n = 100–110) and TMS in combination with simultaneous EEG (TMS-EEG; projected n = 90–95) at baseline, 2 months, and 1 year after surgery.
TMS-EEG participants undergo one session before surgery. A subgroup is invited for a second session 2–4 months after discharge and a third session 12–18 months after discharge. Participants who are unable or decline to participate in TMS-EEG are offered the option to participate in collection of their resting-state EEG only, and subsequently, are invited for second and third EEGs 2 and 12 months after discharge. All study procedures adhered to International Federation of Clinical Neurophysiology guidelines (IFCN) for TMS-EEG studies.24,25
Participants where CSF could not be obtained are invited to undergo an amyloid-PET scan at the one month follow-up visit or thereafter (projected n = 40–50). The rationale for TMS/EEG is to examine brain functioning and plasticity; the rationale for amyloid PET scan is to determine amyloid status in our study patients.
Recruitment and enrollment
Recruitment and enrollment procedures are similar to the first cycle of the SAGES study (SAGES I), which began in 2010 and follow-up is ongoing.12 Permission to approach patients is obtained from the attending surgeon. Eligible patients are identified through daily screening of the operating room advanced booking schedules. Initial screening is conducted using data from the electronic medical record. A letter describing the study and cosigned by the surgeon and the study investigators is sent to eligible participants. Enrollment for SAGES II began on April 1, 2019, and is ongoing.
Unless an opt-out call is received, study staff call the potential participant for a brief telephone screen to explain the study further and to schedule a face-to-face visit in either the participant’s home or at the hospital. Baseline (90 min) and follow-up assessments (45 min) are conducted in participants’ homes. After completion of an eligible surgery, a participant is considered formally enrolled. For all study activities, the date of surgery represents the time of study enrollment (Figure 1).
FIGURE 1.
Enrollment flow and sequence of assessments
Enrollment flow and timing of assessments
The enrollment flow and timing of assessments are detailed in Figure 1. At baseline, prior to surgery, participants complete a comprehensive assessment with variables outlined in Table 2. Interested and eligible participants are scheduled for brain MRI and TMS-EEG. Baseline blood is drawn at the pre-surgical hospital visit or immediately before surgery in the pre-operative holding area. During index hospitalization, CSF is collected at anesthesia induction (for patients undergoing spinal anesthesia). Daily interviews (10–15 min) to assess for delirium are completed throughout the hospital stay and phlebotomy is performed on day 1 and 2 after surgery for biomarker collection. For participants who develop delirium during hospitalization, a two-week follow-up phone call is performed to assess for resolution of delirium. One month after index hospitalization, another home-based assessment is performed, blood collected (either at home or clinic), and interested participants complete a PET scan. Two months after surgery, another home-based assessment is performed and selected participants complete a second TMS-EEG. From 6 to 18 months after surgery, additional home-based assessments are performed every six months with short telephone check-ins in between every 3 months. Family members are interviewed at baseline and every 6 months after index hospitalization to assess participants’ cognition and physical functioning, and report additional hospitalizations or nursing home admissions.
TABLE 2.
Baseline study variables with repeated assessments
Assessments | Baseline | 1 & 2 mos | 6+ mos | Other |
---|---|---|---|---|
Demographic and general descriptors | ||||
Demographics (age, gender, race/ethnicity, education, primary language, marital status, living situation) | P, MR | |||
Cognitive function measures | ||||
Neuropsychological assessment battery26 (NPB) | P | P | P | |
Montreal cognitive assessment27 (MoCA) | P | P | P | |
Subjective/Observed memory problems question | P,C | P | P | |
American national adult reading test28 (AMNART) | P | |||
Informant questionnaire on cognitive decline in the elderly29 (IQCODE) | C | C | ||
Family history of dementia | P | |||
Chart review: Delirium, Dementia, Depression | MR | |||
Clinical variables | ||||
Surgery type | MR | |||
Medical diagnoses | MR | |||
Charlson comorbidity score | MR | |||
APACHE II score | MR | |||
Vascular risk factors (smoking, hypertension, diabetes, hyperlipidemia, vascular dementia) | P | P | P | MR |
Intercurrent illnesses30 | P | P | P | |
Medications | MR | MR | ||
Over-the-counter medications | P | P | P | |
Health habits (alcohol, smoking) | P | |||
Depression (GDS-Short form)31 | P | P | P | |
Subjective health and wellbeing | ||||
Self-rated health32 (MOS SF-12) | P | P | P | |
Quality of life32 (MOS SF-12) | P | P | P | |
Functional variables | ||||
Vision impairment | P | P | ||
Hearing impairment | P | P | ||
Physical function | ||||
PROMIS physical functioning measure33(CAT) | P, C | P | P, C | |
Functional activities questionnaire34 (FAQ) | P, C | P | P, C | |
Falls | P | P | P | |
Activities | ||||
Minnesota leisure time questionnaire35(MLT) | P | P | P | |
Established populations for epidemiologic studies of the elderly activities (EPESE)36 | P | P | P | |
Frailty | ||||
Grip strength (in-person interview only) | P | P (2 mo) | P | |
Timed walk (in-person interview only) | P | P (2 mo) | P | |
Walking self-assessment (for video and phone interview) | P | P (2 mo) | P |
Abbreviations: C, caregiver assessment; MR, medical record; P, patient assessment.
Medical charts are abstracted by a trained study physician after index hospitalization to collect data, including postoperative complications.8
Baseline study variables with repeated assessments
Tables 2–3 describe study variables and their assessment time points. At baseline, demographics and cognitive function are collected, including a complete neuropsychologic test battery and MoCA test. The National Adult Reading Test (AMNART) is administered to assess premorbid intellectual attainment in older adults.28 Participants are asked about subjective memory complaints and the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) is completed with caregivers. We assess clinical and mental health variables delineated in Table 2.
TABLE 3.
Hospital variables, study outcomes, and novel biomarkers with timepoints of assessment
Assessments | Baseline | Hospital (Daily) | 1&2 mos | 6+ mos | Other |
---|---|---|---|---|---|
Hospital and surgery-related variables | |||||
Anesthesia type and duration | MR | ||||
Peri-operative and hospital medications | MR | ||||
American society of anesthesiologists (ASA) class | MR | ||||
Abnormal laboratories (Sodium, potassium, glucose, hematocrit, BUN, Cr) | MR | ||||
Intra-operative hemodynamics and complications | MR | ||||
Brief pain inventory57 | P | P | P | P | |
Quality of sleep | P | P | P | P | |
Delirium measures | |||||
Delirium cognitive screen (Abbreviated testing and DSI)37 | P | P | P | P | |
Confusion assessment method (CAM), long-form | P | P | P | P | |
CAM-Severity (CAM-S), long-form56 | P | P | P | P | |
Family CAM (FAM-CAM)38 | C | C | |||
Delirium Chart Review Method8 | MR | ||||
Long-term cognitive decline | |||||
General cognitive performance (GCP) | P | P | P | ||
Clinical outcomes | |||||
Post-operative complications | MR | ||||
Length of hospital stay | MR | ||||
Rehospitalization | P | P, C | CMS | ||
Nursing home admission | P | P, C | CMS | ||
Death | C/NDI | ||||
Healthcare utilization and costs | CMS | ||||
Novel biomarkers: Biofluids, imaging, electrophysiologic | Timepoints of assessments | ||||
Blood and plasma-based | |||||
Apolipoprotein E | Baseline | ||||
Circulating immune cells | Baseline, POD1 | ||||
Protein biomarkers | Baseline, POD1&2, 1 month | ||||
Cerebrospinal fluid-based (CSF) | |||||
Alzheimer’s disease (AD) biomarkers | Baseline (at anesthesia induction) | ||||
Protein biomarkers | Baseline (at anesthesia induction) | ||||
Imaging-based | |||||
Neuroimaging markers (atrophy and network dysfunction) | Baseline | ||||
Amyloid biomarkers (as measured by PET) | 1–12 months | ||||
Electrophysiologic | |||||
Resting-state EEG | Baseline, 2 months, 1 year | ||||
TMS-EEG network reactivity/connectivity | Baseline, 2 months, 1 year | ||||
TMS-EEG plasticity | Baseline, 2 months, 1 year |
Abbreviations: AD, Alzheimer’s disease; C, Caregiver assessment; CMS, centers for medicare and medicaid services; DOWB, days of the week backwards; DSI, delirium symptom interview; MOYB, months of the year backwards; MR, medical record; NDI, death index; P, patient assessment; PET, positron emission tomography; TMS, transcranial magnetic stimulation.
To assess physical function, we use the Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function (PF) Computerized Adaptive Testing (CAT) item bank for activities of daily living (ADLs).39 We use the Functional Activities Questionnaire (FAQ) to measure instrumental activities of daily living (IADLs); we ask about recent falls and leisure time activities with the Minnesota Leisure Time Activity Questionnaire (MLTAQ).24,39 We assess grip strength with a dynamometer and conduct a six-meter-timed walk test, used to measure Frailty Phenotype.40
Hospital variables, study outcomes, and novel biomarkers (Table 4)
TABLE 4.
Inter-rater reliability for key study variables
Variable | Agreement % | Weighted kappa | 95% CI |
---|---|---|---|
Confusion assessment method (n = 50 paired assessments) | |||
Acute change | 94 | 0.85 | [0.68, 1.00] |
Inattention | 96 | 0.94 | [0.94, 0.94] |
Disorganized thinking | 96 | 0.86 | [0.86, 0.86] |
Altered level of consciousness | 100 | 1.00 | [1.00, 1.00] |
Disorientation | 100 | 1.00 | [1.00, 1.00] |
Memory impairment | 96 | 0.83 | [0.83, 0.83] |
Perceptual disturbance | 98 | 0.66 | [0.03, 1.00] |
Psychomotor agitation | 100 | N/A | N/A |
Psychomotor retardation | 98 | 0.66 | [0.03, 1.00] |
Altered sleep-wake cycle | 88 | 0.76 | [0.58, 0.94] |
CAM delirium | 98 | 0.91 | [0.74, 1.00] |
General cognitive performance (GCP) neuropsychologic battery (n = 25 paired assessments) | |||
In-person | |||
HVLTR - delayed recall | 96 | 1.00 | [1.00, 1.00] |
Digit span forward | 100 | 1.00 | [1.00, 1.00] |
Digit span backward | 96 | 1.00 | [1.00, 1.00] |
VSAT | 91 | 1.00 | [1.00, 1.00] |
Trails B time (secs, N = 24) | 100 | 1.00 | [0.82, 100] |
RBANS digit symbol substitution | 86 | 1.00 | [1.00, 1.00] |
FAS fluency - total words | 68 | 0.99 | [0.99, 0.99] |
Category fluency | 44 | 0.98 | [0.98, 0.98] |
Boston naming test | 96 | 0.83 | [0.52, 1.00] |
Overall GCP score | 68 | 0.99 | [0.94, 1.00] |
Hospital variables
Collected from the electronic health record, hospital variables include anesthesia type/duration, medications, American Society of Anesthesiologists (ASA) Class, abnormal laboratories, intra-operative hemodynamics, and surgical complications. Participants are asked daily about their pain level and sleep quality.
Delirium measures
Delirium is assessed by trained research staff members at baseline, daily in the hospital, and at all follow-up interviews, using the Confusion Assessment Method (CAM), long-form.37 The CAM is rated based on information from patient interviews, including a brief cognitive screen (MoCA, Months of the Year Backwards, Days of the Week Backwards),12 an abbreviated Delirium Symptom Interview (DSI)37 and information on acute mental status change from nurses, or by family members using the Family Confusion Assessment Method (FAM-CAM).38 The CAM is a widely used, standardized method for delirium identification with high sensitivity (94%) and specificity (89%)41 and high inter-rater reliability (kappa = 0.92).14 Combined with a validated chart review method,8,42 patients are classified as delirious if either CAM or chart criteria is met on one or more days during hospitalization to increase sensitivity for detection of delirium. Delirium severity is scored using the CAM-Severity (CAM-S),36 scored 0–19 (19 most severe), a validated severity measure with strong psychometric properties and substantive associations with clinical outcomes. The FAM-CAM, validated against the CAM, had a sensitivity of 88% (95% CI = 47%–99%) and a specificity of 98% (95% CI = 86%–100%).38
Long-term cognitive decline (LTCD)
A comprehensive neuropsychologic test battery12 is administered at baseline and follow-up assessments. The individual neuropsychologic tests include the Hopkins Verbal Learning Test (HVLT), Digit Span Forwards and Backwards, Category Fluency, Phonemic (F-A-S) Fluency Tasks, Boston Naming Test, Visual Search and Attention Test (VSAT), Trail Making Test (A and B), and Digit Symbol Test. We created a weighted composite summary measure, the GCP score, after standard procedures,8 calibrated to a nationally representative sample of older adults43 to yield a mean score = 50 and standard deviation = 10.8,42 The GCP is sensitive to change with minimal floor and ceiling effects,41 and has been applied in many prior studies.7,44,45
Clinical outcomes
Clinical outcomes include post-operative complications, length of hospital stay, nursing home placement, re-hospitalization, healthcare utilization, healthcare costs, and death. The information is collected using patient and caregiver report, medical records, and Medicare data. Death and date of death are confirmed by at least two sources of information through a multi-step procedure, including caregiver interviews, medical record review, obituary review, death certificates, data from Centers for Medicare and Medicaid Services and the National Death Index.
Novel biomarkers
We examine novel AD and inflammatory biomarkers, including blood-based (Apolipoprotein E, inflammatory proteomics, and circulating immune cells), CSF AD, and inflammatory markers, neuroimaging markers, Amyloid Positron Emission Tomography (PET) markers and neurophysiologic (TMS-EEG) markers. The goal is to examine whether delirium, and cognitive decline after delirium, are associated with abnormal CSF AD biomarkers, inflammatory markers, and brain structural or functional abnormalities identified by MRI or TMS-EEG.
Study procedures
Phlebotomy
Plasma biomarkers for AD and neurodegeneration are collected to identify those high risk for delirium and increased delirium severity. SOMAscan (Slow Off-Rate Modified Aptamers), a next generation proteomics platform, will be used to discover new inflammatory proteins46,47 and proteins in other pathophysiologic pathways. Using SAGES II plasma samples, we will validate delirium-related proteins previously identified in SAGES I using SOMAScan, a highly selective single-stranded modified Slow Off-rate Modified DNA Aptamers (SOMAmer) (SomaLogic; Boulder, CO). Thus, SAGES II will serve as an independent validation set for the SAGES I SOMAscan findings. For validation using SAGES II samples, we will use standard enzyme-linked immunosorbent assays (ELISA) or the Ella platform (ProteinSimple; San Jose, CA). We plan to measure inflammatory proteins using a previously developed inflammatory index, the Walston Index, which is a combination of IL-6 and soluble tumor necrosis factor-alpha-receptor-1 (sTNFR1).48 Circulating peripheral blood mononuclear cells (PBMCs) are isolated from blood and fixed. PBMCs harvested from patients with and without delirium are examined using CyTOF, a state-of-the-art mass cytometry platform for single cell immunophenotyping, to determine if delirious patients have more pro-inflammatory cellular profiles. We will use next-generation flow cytometry, CyTOF (Fluidigm), to characterize types of PBMCs associated with delirium and to simultaneously quantify expression of a large number of key functional markers in well-defined subsets of these cells. We will use a panel of metal-tagged antibodies targeting 29 cell surface proteins for all major immune cell types and up to 16 phosphoepitopes associated with key intracellular signaling proteins for clinical recovery from surgery. We will define major immune cell subpopulations (e.g., neutrophils, monocytes, CD4 T cells, CD8 T cells, NK, and DCs) and their activation/differentiation status using manual gating and unsupervised learning tools available through Cytobank. CyTOF combined with machine learning techniques allows a comprehensive and simultaneous assessment of expression of up to 45 phenotypic and functional markers in all major immune cell subsets at single-cell resolution, and can describe the diversity of immune cell subsets as well as define their state of activation, frequency, abundance, and ratios with precision.
Blood is collected from all SAGES II participants at four time points: baseline, postoperative days 1 and 2 (POD1, POD2), and 1 month after surgery. Because our study was focused on acute risk factors for delirium, blood biomarkers were not collected after one-month follow-up. Blood samples are collected via peripheral venipuncture or central venous line (if available) and during routine clinical phlebotomy, whenever possible. If a patient is discharged on the day of surgery, blood is obtained prior to discharge from the post-anesthesia care unit.
Cerebrospinal fluid (CSF)
CSF is collected to examine the relationship between baseline CSF AD biomarkers (CSF Aβ40, Aβ42, total tau [t-tau], phospho-tau/Aβ42 ratios, and neurofilament light [NFL]) and development of post-operative delirium and LTCD. CSF is acquired during induction of spinal anesthesia, immediately pre-operatively, and at one month post-operatively via research lumbar puncture. CSF was collected by dropwise collection or aspiration directly into the collection tubes. Samples were transported on ice and were centrifuged at low speed (1000 rcf for 10 min), divided into aliquots, and frozen immediately in low-absorption polyprophylene cryotubes at −80°C. Quality control measures were in place at each step to assure rapid and appropriate handling of all specimens. The CSF will be used to develop a novel multi-protein inflammatory index for delirium similar to our prior function utilizing multiple inflammatory biomarkers and the Walston Index.48 If CSF was not obtained at anesthesia induction, participants were invited to undergo postsurgical amyloid PET scan to help collect some information on AD biomarkers.
Neurophysiology (TMS/EEG)
All patients who agree will receive TMS/EEG as a probe of brain functioning to determine whether abnormal brain network reactivity/connectivity and altered mechanisms of cortical plasticity as characterized by TMS/EEG are associated with the risk of developing delirium. For EEG, a cap with electrodes is placed on the participant’s head to measure electrical brain activity.49 For TMS, a coil is placed against the participant’s head to produce a magnetic field that briefly affects brain function.49 Participants undergo resting-state EEG recording for 3 min each in the eyes-open and eyes-closed conditions. Participants then receive single-pulse TMS applied to up to four cortical regions, including the left dorsolateral prefrontal cortex (DLPFC), left inferior parietal lobe (IPL), left superior parietal lobe (SPL), and left primary motor cortex (M1), with simultaneous EEG and (in M1 only) electromyography (EMG) and with sham single-pulse TMS applied to control for specific effects.50 Subsequently, to index mechanisms of plasticity, participants receive intermittent theta-burst stimulation (iTBS) to M1 followed by repeated single pulse stimulation with EEG–EMG measurements. Where available, structural MRI is used to determine the targets of stimulation for the TMS-EEG procedures, with the precise targets determined based on connectome-based resting-state fMRI network connectivity accommodated to individual anatomy,49 and with online neuro-navigation to ensure accurate targeting. Neuro-navigation refers to using MRI neuroimaging to guide electrode placement for TMS. In cases where individual MRI is not available, stimulation is directed to the closest EEG electrode. Physiologic biomarkers of cerebral oscillatory function, cortical reactivity, network effective connectivity, and cortical plasticity51 are extracted to evaluate the associations with delirium, delirium severity, and LTCD.
Neuroimaging (MRI)
Structural and functional MRI scans are used to examine neuroimaging biomarkers of preclinical AD, vulnerable aging, and possible links to molecular biomarkers of pathology measured in CSF and plasma. MRI scans are acquired using a 3T scanner before index hospitalization. The MRI acquisition protocol includes anatomical, diffusion, and resting-state functional MRI with parameters that approximate those used in the Alzheimer’s Disease Neuroimaging Initiative (ADNI 3).
Amyloid PET scans
F18Florbetapir PET is acquired with a 370 MBq (10.0 mCi) ± 10% bolus injection followed by 20 min (4 × 5 min frames) acquisition at 50–70 min post-injection, after acquisition protocols used in ADNI 3.52 Participants are scanned on a Siemens Biograph m64 time-of-flight PET/CT.
Data collection procedures and quality assurance
Interviewer standardization
Each study research assistant undergoes 3–4 weeks of intensive training, including didactics with item-by-item instructions for all interview questions, practice interviews with peers, and standardization. New staff members are instructed by experienced interviewers, conduct practice interviews, shadow experienced interviewers, and then conduct five interviews although evaluated by experienced team members. To conduct interviews independently, a trainee needs to conduct at least two observed interviews error-free.
Data quality assurance
For data quality assurance to achieve completeness of data (minimal missing data) with accuracy (minimal errors), consistency (stable values), and timeliness, we apply the same approaches described previously for SAGES I.13 These include staff training, meetings to address coding questions, inter-rater reliability assessments, database programming and cross-checking, and regular review of data quality reports.
Data management
Data management is facilitated with electronic data entry using REDCap®,53,54 which includes real-time alerts for missed and out-of-range data. In addition, peer re-checks for all data entry are conducted. Reporting tools using R-statistical software linked to the REDCap datasets provide real-time updates about all study activities completed, expected timeframe for completion, or missed timely completion.
Inter-rater reliability testing
Table 4 shows the inter-rater reliability assessment results for delirium (CAM ratings, n = 50 paired assessments) and GCP (neuropsychologic battery, n = 25 paired assessments) with percent agreement, weighted kappa, and 95% confidence intervals at item and summary score levels. For overall CAM delirium score, weighted kappa was 0.91, and individual CAM features showed weighted kappas ranging from 0.66 (perceptual disturbance and psychomotor retardation) to 1.0 (altered level of conciseness and disorientation). Weighted kappas for the four core features of the CAM algorithm ranged between 0.85 and 1.0. Discrepancies on CAM ratings were most often due to subtle symptoms where there was disagreement in coding between interviewers. Weighted kappa was high for summary GCP score with 0.99 and on the item level from 0.83 (Boston Naming Test) to 1.0 (HVLTR-Delayed recall, Digit Span forward/ backward, VSAT, RBANS). Discrepancies within test ratings were due to mislabeling of one answer on the Boston Naming Test or minor miscounting on the Category Fluency Test.
Power analysis and sample size calculations
The cohort sample size (n = 400–420) was determined to, in general, provide 80–90 percent power to detect clinically meaningful differences in the study groups for each subproject. For example, we estimated that we will be able to detect with 80% power, a correlation between delirium severity and cognitive decline of ≥0.25 compared with a null hypothesis of 0 correlation with a Type-I error rate of 5%. Therefore, we will have sufficient sample size to detect even a small correlation between delirium severity and rate of cognitive decline, within a range that is of clinical relevance. We conducted similar power estimates for all planned sub-studies, and estimated adequate power to meet our study aims.
COVID-19 adaptations
During the COVID-19 shut-down, in-person interviews were adapted to video (iPads delivered to participants’ homes contact-free) or telephone interviews. Video-based interviews were similar to in-person interviews with the exception that grip strength and timed walk tests could not be completed, and self-reported problems with vision, hearing, and walking were substituted for direct assessment of these areas. For phone assessments, the Telephone MoCA55 was used instead of the Full MoCA, and the Boston Naming Test and Trails A and B were substituted with oral tests. The Visual Search and Attention Test and RBANS did not have an acceptable telephone substitute and had to be omitted from telephone administration. Validations of the alternate assessment strategies are underway. We will carefully assess the impact of these adaptations quantitatively. For instance, we will evaluate inter-correlation of alternate forms of measures (such as T-MOCA vs. full MOCA), and alternate forms of measures for vision and hearing (such as in-person testing vs. self-report), and we will harmonize measures as appropriate. We are currently conducting validation studies of alternate modes of administering neuropsychologic tests in a subgroup that received the different modes in close temporal proximity (e.g., telephone vs. video). The main results of the pandemic are mild delays and slight decrease in final numbers of participants. All SAGES II data will be available to share via the NIA Biobank once the study is completed.
Proposed statistical analysis
Given that the main aims of this study are to examine novel risk factors and biomarkers for delirium and its associated LTCD, our planned analyses will incorporate these multiple novel predictors. Thus, we plan to examine the relationship between AD biomarkers, inflammatory markers, neuroimaging markers, and neurophysiologic markers of plasticity and connectivity with both delirium and with LTCD. As an example, we will examine CSF biomarkers for Alzheimer’s Dementia and their correlation with incident delirium. We will use predictive modeling, logistic regression, and piecewise linear mixed-effect modeling to analyze these relationships.
DISCUSSION
SAGES II provides an innovative approach to examining delirium and its inter-relationship with dementia. Identification of risk factors, hospital variables, novel biomarkers—blood-based, CSF-based, neuroimaging and electrophysiologic—associated with delirium, complicated delirium, and LTCD will allow us to better understand the pathophysiology and outcomes of delirium and to appropriately target vulnerable patients before surgery.
There are unique strengths to this study. SAGES II represents a comprehensive and advanced study with pre-operative, post-operative, and long-term follow-up on a longitudinal cohort of older patients undergoing major surgery. Few studies offer the multi-faceted breadth of assessments of SAGES II, with in-depth clinical characterization, cognitive measures over time, and biomarkers. In particular, we measure novel biomarkers for delirium in blood and CSF, neuroimaging markers, neurophysiologic measurements, and life-course factors (educational attainment, reading level) using cutting edge approaches. Second, we examine patient-centered outcomes, such as depression, self-rated health, quality of life, and caregiver assessments longitudinally; details of these assessments are in Table 2. Third, through identification and evaluation of key indicators of brain vulnerability and their relationship to delirium, SAGES II represents a concerted effort to enhance understanding of delirium pathophysiology, an area that remains poorly understood. Moreover, the focus on understanding delirium that leads to long-term cognitive impairment (i.e., complicated delirium) is a major advance, that will allow clinicians and researchers to target interventions for identified risk factors to the most vulnerable patients. Lastly, SAGES I and II will provide a valuable database and biorepository for future research.
Several limitations are important to note. The patient recruitment catchment area is limited to a single geographic location in New England and participants are healthy enough for elective surgery. These factors may limit generalizability of our findings, and future function is needed to replicate the results in other regions and in broader populations. Our primary outcome is LTCD, which may not necessarily reflect clinical diagnoses of dementia. Finally, we are not using the important consensus nomenclature for perioperative neurocognitive disorders,56 because we are interested in cognitive decline that is related to delirium and extends beyond 12 months, which are not directly covered by the nomenclature.
CONCLUSIONS
The SAGES II study lays the groundwork for important future studies based on this comprehensive cohort. Our overarching hypothesis is that delirium may be a significant initiating and/or predisposing factor for LTCD and that patient and hospitalization-specific factors are important additional contributors to delirium and cognitive impairment. In addition, delirium may serve as a marker of pre-existing factors that put patients at increased risk of LTCD and dementia. We anticipate that timely interventions and recognition of risk factors for delirium can prevent LTCD and dementia, and will ultimately, allow us to improve clinical care for older adults.
Supplementary Material
Figure S1. A unifying conceptual framework for the study demonstrating the complex interface between delirium and dementia, and our unified investigation of key potential pathophysiologic pathways.
Key points.
The Successful Aging after Elective Surgery (SAGES) II study is a 5-year prospective observational study of 420 community dwelling older persons, prior to scheduled surgery, and followed during hospitalization through 18 months post-operatively.
The SAGES II study examines the pathophysiology and inter-relationship between delirium and dementia.
We examine novel biomarkers potentially associated with delirium—inflammation, Alzheimer’s disease (AD) pathology and neurodegeneration, neuroimaging markers, and neurophysiologic markers—and other clinical outcomes.
The goal of this paper is to describe the complex study design and methods for the SAGES II study which integrates MRI, TMS/EEG, PET modalities, and high-quality longitudinal data.
Why does this paper matter?
The SAGES II study is an important prospective cohort study, and this paper will be the basis for all future work from this innovative gerontologic research.
ACKNOWLEDGMENTS
This paper is dedicated to the memory of Joshua Bryan Inouye Helfand.
SPONSOR’S ROLE
No sponsors were used for this project/study. The funder had no role in the manuscript.
FUNDING INFORMATION
In part by grants from the National Institute on Aging grants no. P01AG031720 (Sharon K. Inouye), R33AG071744 (Sharon K. Inouye), R01AG044518 (Sharon K. Inouye/Richard N. Jones). Dr. Marcantonio’s time was supported in part by grants no. K24AG035075 (Edward R. Marcantonio) and R01AG030618; Drs. Marcantonio and Libermann’s time was supported in part by grant no. R01AG051658. Dr. Fong’s time was supported in part by grant no. R21AG057955. Dr. Inouye holds the Milton and Shirley F. Levy Family Chair at Hebrew SeniorLife/Harvard Medical School.
Abbreviations:
- BIDMC
Beth Israel Deaconess Medical Center
- BWH
Brigham and Women’s Hospital
- BWFH
Brigham and Women’s Faulkner Hospital
- HMS
Harvard Medical School; HSL, Hebrew Seniorlife
- MGH
Massachusetts General Hospital
- PI
Principal Investigator
APPENDIX A: SAGES II study group
[Presented in alphabetical order; individuals listed may be part of multiple groups, but are listed only once under major activity, listed in parentheses].
Overall Principal Investigator: Sharon K. Inouye, MD, MPH (Overall PI, Administrative Core, Project 1; HSL, BIDMC, HMS).
Project and Core Leaders: Bradford Dickerson, MD (Project 3; MGH, HMS); Richard Jones, ScD (Data Core, Project 4; Brown University); Towia Libermann, PhD (Project 2, BIDMC, HMS); Edward R. Marcantonio, MD, SM (Overall Co-PI, Epidemiology Core, Project 2; BIDMC, HMS), Alvaro Pascual-Leone, MD, PhD (Project 5, HSL, HMS); Mouhsin Shafi, MD, PhD (Project 5, HMS, BIDMC). Thomas Travison, PhD (Data Core, HSL, HMS);
Executive Committee: Michele Cavallari, MD, PhD (BWH); Simon T. Dillon, PhD (HMS, BIDMC); Tamara Fong, MD, PhD (HSL, BIDMC, HMS,); Eva M. Schmitt, PhD (Overall Project Director, HSL); Alexandra Touroutoglou, PhD (MGH, HMS).
Other Co-investigators: David Alsop, PhD (Project 3; BIDMC, HMS); Steven Arnold, MD, (MGH, HMS); Becky Catherine Carlyle, PhD (MGH); Tammy Hshieh, MD, MPH (BWH, HMS); Yuta Katsumi, PhD (MGH), Long Ngo, PhD (BIDMC, HMS); Jessica Ross, PhD (BIDMC), Emiliano Santarnecchi, PhD (BIDMC, MGH); Sarinnapha Vasunilashorn, PhD (HMS, BIDMC, HMS).
Clinical Consensus Panel: Franchesca Arias, PhD (BIDMC, HMS); Eyal Kimchi, MD (MGH, HMS), Eran Metzger, MD, (HSL, BIDMC, HMS); Jason Strauss, MD (Cambridge Health Alliance); Bonnie Wong, PhD (MGH, HMS, MGH).
Surgical and Anesthesia Leaders: Ayesha Abdeen, MD (HMS, BIDMC); Brandon Earp, MD (BWFH, HMS); Lisa Kunze, MD (HMS, BIDMC); Jeffrey Lange, MD (BWH, HMS); Marc Schermerhorn, MD (HMS, BIDMC); David Shaff, MD (BWFH, HMS); Kamen Vlassakov, MD (BWH, HMS).
Epidemiology Core: Maja Burch (BIDMC) Rejoice Dhliwayo (BIDMC), Amanda Gallagher (HSL); Grace Going (HSL), Brenna Hagan (BIDMC), Yonah Joffe (HSL), Sofia Kirkman (BIDMC), Shu Jing Lian (BIDMC), Julianna Liu (HSL); Molly Mackler (HSL); Madeleine Martine (HSL); Gina Michael (BIDMC), Jacqueline Nee (HSL), Nancy Otaluka (BIDMC), Kerry Palihnich (BIDMC), Fotini Papadopoulou (BIDMC), Lauren Phung (BIDMC), Christopher Ramirez, (MGH); Andrei Rodionov, PhD (BIDMC), Louis Shaevel (BIDMC), Meghan Shanahan (HSL), Bianca Trombetta, (MGH); Stephanie Waldman (BIDMC), Peter Wang (BIDMC), Michelle Ward (BIDMC), Guoquan Xu (HSL).
Data Management and Statistical Analysis Core: Fan Chen (HSL) Yun Gou, MA (HSL); Benjamin Helfand, MSc, MD/PhD (University of Massachusetts Medical School); Yoojin Jung, PhD (BIDMC); Zachary Kunicki, PhD (Brown University); Douglas Tommet, MPH (Brown University).
Footnotes
CONFLICT OF INTEREST
All the co-authors fully disclose they have no financial interests, activities, relationships, and affiliations. The co-authors also declare they have no potential conflicts from the three years prior to submission of this manuscript.
The members of the SAGES II study team are provided in Appendix.
SUPPORTING INFORMATION
Additional supporting information can be found online in the Supporting Information section at the end of this article.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Figure S1. A unifying conceptual framework for the study demonstrating the complex interface between delirium and dementia, and our unified investigation of key potential pathophysiologic pathways.