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Background: Recent studies have reported an association between presurgical frailty and postoperative delirium. However, it remains unclear whether the frailty‐delirium relationship differs by measurement tool (e.g., frailty index vs. frailty phenotype) and whether frailty is associated with delirium, independent of preoperative cognition. Methods: We used the successful aging after elective surgery (SAGES) study, a prospective cohort of older adults age ≥70 undergoing major non‐cardiac surgery (N = 505). Preoperative measurement of the modified mini‐mental (3MS) test, frailty index and frailty phenotype were obtained. The confusion assessment method (CAM), supplemented by chart review, identified postoperative delirium. Delirium feature severity was measured by the sum of CAM‐severity (CAM‐S) scores. Generalized linear models were used to determine the relative risk of each frailty measure with delirium incidence and severity. Subsequent models adjusted for age, sex, surgery type, Charlson comorbidity index, and 3MS. Results: On average, patients were 76.7 years old (standard deviation 5.22), 58.8% of women. For the frailty index, the incidence of delirium was 14% in robust, 17% in prefrail, and 31% in frail patients (p < 0.001). For the frailty phenotype, delirium incidence was 13% in robust, 21% in prefrail, and 27% in frail patients (p = 0.016). Frailty index, but not phenotype, was independently associated with delirium after adjustment for comorbidities (relative risk [RR] 2.13, 95% confidence interval [CI] 1.23–3.70; RR 1.61, 95% CI 0.77–3.37, respectively). Both frailty measures were associated with delirium feature severity. After adjustment for preoperative cognition, only the frailty index was associated with delirium incidence; neither index nor phenotype was associated with delirium feature severity. Conclusion: Both the frailty index and phenotype were associated with the development of postoperative delirium. The index showed stronger associations that remained significant after adjusting for baseline comorbidities and preoperative cognition. Measuring frailty prior to surgery can assist in identifying patients at risk for postoperative delirium. See related Editorial by Callahan and Kuchel in this issue. [ABSTRACT FROM AUTHOR]

Background: The Successful Aging after Elective Surgery (SAGES) II Study was designed to examine the relationship between delirium and Alzheimer's disease and related dementias (AD/ADRD), by capturing novel fluid biomarkers, neuroimaging markers, and neurophysiological measurements. The goal of this paper is to provide the first complete description of the enrolled cohort, which details the baseline characteristics and data completion. We also describe the study modifications necessitated by the COVID‐19 pandemic, and lay the foundation for future work using this cohort. Methods: SAGES II is a prospective observational cohort study of community‐dwelling adults age 65 and older undergoing major non‐cardiac surgery. Participants were assessed preoperatively, throughout hospitalization, and at 1, 2, 6, 12, and 18 months following discharge to assess cognitive and physical functioning. Since participants were enrolled throughout the COVID‐19 pandemic, procedural modifications were designed to reduce missing data and allow for high data quality. Results: About 420 participants were enrolled with a mean (standard deviation) age of 73.4 (5.6) years, including 14% minority participants. Eighty‐eight percent of participants had either total knee or hip replacements; the most common surgery was total knee replacement with 210 participants (50%). Despite the challenges posed by the COVID‐19 pandemic, which required the use of novel procedures such as video assessments, there were minimal missing interviews during hospitalization and up to 1‐month follow‐up; nearly 90% of enrolled participants completed interviews through 6‐month follow‐up. Conclusion: While there are many longitudinal studies of older adults, this study is unique in measuring health outcomes following surgery, along with risk factors for delirium through the application of novel biomarkers—including fluid (plasma and cerebrospinal fluid), imaging, and electrophysiological markers. This paper is the first to describe the characteristics of this unique cohort and the data collected, enabling future work using this novel and important resource. [ABSTRACT FROM AUTHOR]

This editorial comments on the articles by Tang et al. and Reich et al. in this issue. [ABSTRACT FROM AUTHOR]

Introduction: One‐year health‐care costs associated with delirium in older hospitalized patients with and without Alzheimer's disease and related dementias (ADRD) have not been examined previously. Methods: Medicare costs were determined prospectively at discharge, and at 30, 90, and 365 days in a cohort (n = 311) of older adults after hospital admission. Results: Seventy‐six (24%) patients had ADRD and were more likely to develop delirium (51% vs. 24%, P < 0.001) and die within 1 year (38% vs. 21%, P = 0.002). In ADRD patients with versus without delirium, adjusted mean difference in costs associated with delirium were $34,828; most of the excess costs were incurred between 90 and 365 days (P = 0.03). In non‐ADRD patients, delirium was associated with increased costs at all timepoints. Excess costs associated with delirium in ADRD patients increased progressively over 1 year, whereas in non‐ADRD patients the increase was consistent across time periods. Discussion: Our findings highlight the complexity of health‐care costs for ADRD patients who develop delirium, a potentially preventable source of expenditures. Highlights: Novel examination of health‐care costs of delirium in persons with and without Alzheimer's disease and related dementias (ADRD).Increased 1‐year costs of $34,828 in ADRD patients with delirium (vs. without).Increased costs for delirium in ADRD occur later during the 365‐day study period.For ADRD patients, cost differences between those with and without delirium increased over 1 year.For non‐ADRD patients, the parallel cost differences were consistent over time. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Deficits in cholinergic function have been postulated to cause delirium and cognitive decline. This review examines current understanding of the cholinergic deficiency hypothesis in delirium by synthesizing evidence on potential pathophysiological pathways. Acetylcholine synthesis involves various precursors, enzymes, and receptors, and dysfunction in these components can lead to delirium. Insults to the brain, like ischemia and immunological stressors, can precipitously alter acetylcholine levels. Imbalances between cholinergic and other neurotransmitter pathways may result in delirium. Furthermore, genetic, enzymatic, and immunological overlaps exist between delirium and dementia related to the cholinergic pathway. Important areas for future research include identifying biomarkers, determining genetic contributions, and evaluating response to cholinergic drugs in delirium. Understanding how the cholinergic pathway relates to delirium may yield innovative approaches in the diagnosis, prevention, and treatment of this common, costly, and morbid condition. Key Words: Acetylcholine--Delirium--Delirium in older persons--Dementia--Cholinergic deficiency.

Background: The ability to rate delirium severity is key to providing optimal care for persons with Alzheimer's Disease and Related Dementias (ADRD). Such ratings would allow clinicians to assess response to treatment, recovery time and prognosis, nursing burden and staffing needs, and to provide nuanced, appropriate patient‐centered care. Given the lack of existing tools, we defined content domains for a new delirium severity instrument for use in individuals with mild to moderate ADRD, the DEL‐S‐AD. Methods: We built upon our previous study in which we created a content domain framework to inform development of a general delirium severity instrument, the DEL‐S. We engaged a new expert panel to discuss issues of measurement in delirium and dementia and to determine which content domains from the prior framework were useful in characterizing delirium severity in ADRD. We also asked panelists to identify new domains. Our panel included eight interdisciplinary members with expertise in delirium and dementia. Panelists participated in two rounds of review followed by two surveys over 2 months. Results: Panelists endorsed the same content domains as for general delirium severity, including Cognitive, Level of Consciousness, Inattention, Psychiatric‐Behavioral, Emotional Dysregulation, Psychomotor Features, and Functional; however, they excluded six of the original subdomains which they considered unhelpful in the context of ADRD: cognitive impairment; anxiety; fear/sense of unease; depression; gait/walking; and incontinence. Debated measurement challenges included assessment at one point in time versus over time, accounting for differences in clinical settings, and accurate assessment of symptoms related to delirium versus dementia. Conclusions: By capturing a range of characteristics of delirium severity potentially present in patients with ADRD, a population that may already have attention, functional, and emotional changes at baseline, the DEL‐S‐AD provides a novel rating tool that will be useful for clinical and research purposes to improve patient care. [ABSTRACT FROM AUTHOR]