Relationship between cortical brain atrophy, delirium, and long-term cognitive decline in older surgical patients.

In older patients, delirium after surgery is associated with long-term cognitive decline (LTCD). The neural substrates of this association are unclear. Neurodegenerative changes associated with dementia are possible contributors. We investigated the relationship between brain atrophy rates in Alzheimer's disease (AD) and cognitive aging signature regions from magnetic resonance imaging before and one year after surgery, LTCD assessed by the general cognitive performance (GCP) score over 6 years post-operatively, and delirium in 117 elective surgery patients without dementia (mean age = 76). The annual change in cortical thickness was 0.2(1.7) % (AD-signature p = 0.09) and 0.4(1.7) % (aging-signature p = 0.01). Greater atrophy was associated with LTCD (AD-signature: beta(CI) = 0.24(0.06-0.42) points of GCP/mm of cortical thickness; p < 0.01, aging-signature: beta(CI) = 0.55(0.07-1.03); p = 0.03). Atrophy rates were not significantly different between participants with and without delirium. We found an interaction with delirium severity in the association between atrophy and LTCD (AD-signature: beta(CI) = 0.04(0.00-0.08), p = 0.04; aging-signature: beta(CI) = 0.08(0.03-0.12), p < 0.01). The rate of cortical atrophy and severity of delirium are independent, synergistic factors determining postoperative cognitive decline in the elderly.

Biomarkers of neurodegeneration and neural injury as potential predictors for delirium.

OBJECTIVES: Determine if biomarkers of Alzheimer's disease and neural injury may play a role in the prediction of delirium risk. METHODS: In a cohort of older adults who underwent elective surgery, delirium case-no delirium control pairs (N = 70, or 35 matched pairs) were matched by age, sex and vascular comorbidities. Biomarkers from CSF and plasma samples collected prior to surgery, including amyloid beta (Aß)42 , Aß40 , total (t)-Tau, phosphorylated (p)-Tau181 , neurofilament-light (NfL), and glial fibrillary acid protein (GFAP) were measured in cerebrospinal fluid (CSF) and plasma using sandwich enzyme-linked immunosorbent assays (ELISAs) or ultrasensitive single molecule array (Simoa) immunoassays. RESULTS: Plasma GFAP correlated significantly with CSF GFAP and both plasma and CSF GFAP values were nearly two-fold higher in delirium cases. The median paired difference between delirium case and control without delirium for plasma GFAP was not significant (p = 0.074) but higher levels were associated with a greater risk for delirium (odds ratio 1.52, 95% confidence interval 0.85, 2.72 per standard deviation increase in plasma GFAP concentration) in this small study. No matched pair differences or associations with delirium were observed for NfL, p-Tau 181, Aß40 and Aß42 . CONCLUSIONS: These preliminary findings suggest that plasma GFAP, a marker of astroglial activation, may be worth further investigation as a predictive risk marker for delirium.

Sex-specific pleiotropic changes in emotional behavior and alcohol consumption in human α-synuclein A53T transgenic mice during early adulthood.

Point mutations in the α-synuclein coding gene may lead to the development of Parkinson's disease (PD). PD is often accompanied by other psychiatric conditions, such as anxiety, depression, and drug use disorders, which typically emerge in adulthood. Some of these point mutations, such as SNCA and A30T, have been linked to behavioral effects that are not commonly associated with PD, especially regarding alcohol consumption patterns. In this study, we investigated whether the familial PD point mutation A53T is associated with changes in alcohol consumption behavior and emotional states at ages not yet characterized by α-synuclein accumulation. The affective and alcohol-drinking phenotypes remained unaltered in female PDGF-hA53T-synuclein-transgenic (A53T) mice during both early and late adulthood. Brain region-specific activation of ceramide-producing enzymes, acid sphingomyelinase (ASM), and neutral sphingomyelinase (NSM), known for their neuroprotective properties, was observed during early adulthood but not in late adulthood. In males, the A53T mutation was linked to a reduction in alcohol consumption in both early and late adulthood. However, male A53T mice displayed increased anxiety- and depression-like behaviors during both early and late adulthood. Enhanced ASM activity in the dorsal mesencephalon and ventral hippocampus may potentially contribute to these adverse behavioral effects of the mutation in males during late adulthood. In summary, the A53T gene mutation was associated with diverse changes in emotional states and alcohol consumption behavior long before the onset of PD, and these effects varied by sex. These alterations in behavior may be linked to changes in brain ceramide metabolism.

A Novel Approach to Monitoring Cognitive Adverse Events for Interventional Studies Involving Advanced Dementia Patients: Insights From the Electroconvulsive Therapy for Agitation in Dementia Study.

OBJECTIVE: To develop an individualized method for detecting cognitive adverse events (CAEs) in the context of an ongoing trial of electroconvulsive therapy for refractory agitation and aggression for advanced dementia (ECT-AD study). METHODS: Literature search aimed at identifying (a) cognitive measures appropriate for patients with advanced dementia, (b) functional scales to use as a proxy for cognitive status in patients with floor effects on baseline cognitive testing, and (c) statistical approaches for defining a CAE, to develop CAEs monitoring plan specifically for the ECT-AD study. RESULTS: Using the Severe Impairment Battery-8 (SIB-8), baseline floor effects are defined as a score of ≤5/16. For patients without floor effects, a decline of ≥6 points is considered a CAE. For patients with floor effects, a decline of ≥30 points from baseline on the Barthel Index is considered a CAE. These values were derived using the standard deviation index (SDI) approach to measuring reliable change. CONCLUSIONS: The proposed plan accounts for practical and statistical challenges in detecting CAEs in patients with advanced dementia. While this protocol was developed in the context of the ECT-AD study, the general approach can potentially be applied to other interventional neuropsychiatric studies that carry the risk of CAEs in patients with advanced dementia.

Successful aging after elective surgery II: Study cohort description.

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.

Association of Loneliness With Change in Physical and Emotional Health of Older Adults During the COVID-19 Shutdown.

OBJECTIVES: To examine factors influencing loneliness and the effect of loneliness on physical and emotional health, in the context of the COVID-19 pandemic. DESIGN: Prospective, observational cohort. SETTING: Community-dwelling participants. PARTICIPANTS: Older adults (n = 238) enrolled in a longitudinal study. MEASUREMENTS: Interviews were completed July-December 2020. Loneliness was measured with the UCLA 3-item loneliness scale. Data including age, marriage, education, cognitive functioning, functional impairment, vision or hearing impairment, depression, anxiety, medical comorbidity, social network size, technology use, and activity engagement were collected. Health outcomes included self-rated health, and physical and mental composites from the 12-item Short Form Survey. Physical function was measured by a PROMIS-scaled composite score. RESULTS: Thirty-nine (16.4%) participants reported loneliness. Vulnerability factors for loneliness included age (RR = 1.08, 95% CI 1.02-1.14); impairment with instrumental activities of daily living (RR = 2.08, 95% CI 1.14-3.80); vision impairment (RR = 2.09, 95% CI 1.10-3.97); depression (RR = 1.34, 95% CI 1.25-1.43); and anxiety (RR = 1.92, 95% CI 1.55-2.39). Significant resilience factors included high cognitive functioning (RR = 0.88, 95% CI 0.83-0.94); large social network size (RR = 0.92, 95% CI 0.88-0.96); technology use (RR = 0.81, 95% CI 0.73-0.90); and social and physical activity engagement (RR = 0.91, 95% CI 0.85-0.98). Interaction analyses showed that larger social network size moderated the effect of loneliness on physical function (protective interaction effect, RR = 0.64, 95% CI 0.15-1.13, p <.01), and activity engagement moderated the effect of loneliness on mental health (protective interaction effect, RR = 0.65, 95% CI 0.25-1.05, p <.001). CONCLUSIONS: Resilience factors may mitigate the adverse health outcomes associated with loneliness. Interventions to enhance resilience may help to diminish the detrimental effects of loneliness and hold great importance for vulnerable older adults.

Comparison of the frailty index and frailty phenotype and their associations with postoperative delirium incidence and severity.

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.

Clinicians' Perceptions of a Modified Hospital Elder Life Program for Delirium Prevention During COVID-19.

The Hospital Elder Life Program (HELP) is a multicomponent delirium prevention program targeting delirium risk factors of cognitive impairment, vision and hearing impairment, malnutrition and dehydration, immobility, sleep deprivation, and medications. We created a modified and extended version of the program, HELP-ME, deployable under COVID-19 conditions, for example, patient isolation and restricted staff and volunteer roles. We explored perceptions of interdisciplinary clinicians who implemented HELP-ME to inform its development and testing. This was a qualitative descriptive study of HELP-ME among older adults on medical and surgical services during the COVID-19 pandemic. Participants included HELP-ME staff at 4 pilot sites across the United States who implemented HELP-ME.We held five 1-hour video focus groups (5-16 participants/group) to review specific intervention protocols and the overall program. We asked participants open-endedly about positive and challenging aspects of protocol implementation. Groups were recorded and transcribed. We used directed content analysis to analyze data. Participants identified general, technology-related, and protocol-specific positive and challenging aspects of the program. Overarching themes included the need for enhanced customization and standardization of protocols, need for increased volunteer staffing, digital access to family members, patient technological literacy and comfort, variation in the feasibility of remote delivery among intervention protocols, and preference for a hybrid program model. Participants offered related recommendations. Participants felt that HELP-ME was successfully implemented, with some modifications needed to address limitations of remote implementation. A hybrid model combining remote and in-person aspects was recommended as the preferred option.

Caffeine, Postoperative Delirium And Change In Outcomes after Surgery (CAPACHINOS)-2: protocol for a randomised controlled trial.

INTRODUCTION: Delirium is a major public health issue for surgical patients and their families because it is associated with increased mortality, cognitive and functional decline, prolonged hospital admission and increased healthcare expenditures. Based on preliminary data, this trial tests the hypothesis that intravenous caffeine, given postoperatively, will reduce the incidence of delirium in older adults after major non-cardiac surgery. METHODS AND ANALYSIS: The CAffeine, Postoperative Delirium And CHange In Outcomes after Surgery-2 (CAPACHINOS-2) Trial is a single-centre, placebo-controlled, randomised clinical trial that will be conducted at Michigan Medicine. The trial will be quadruple-blinded, with clinicians, researchers, participants and analysts all masked to the intervention. The goal is to enrol 250 patients with a 1:1:1: allocation ratio: dextrose 5% in water placebo, caffeine 1.5 mg/kg and caffeine 3 mg/kg as a caffeine citrate infusion. The study drug will be administered intravenously during surgical closure and on the first two postoperative mornings. The primary outcome will be delirium, assessed via long-form Confusion Assessment Method. Secondary outcomes will include delirium severity, delirium duration, patient-reported outcomes and opioid consumption patterns. A substudy analysis will also be conducted with high-density electroencephalography (72-channel system) to identify neural abnormalities associated with delirium and Mild Cognitive Impairment at preoperative baseline. ETHICS AND DISSEMINATION: This study was approved by the University of Michigan Medical School Institutional Review Board (HUM00218290). An independent data and safety monitoring board has also been empanelled and has approved the clinical trial protocol and related documents. Trial methodology and results will be disseminated via clinical and scientific journals along with social and news media. TRIAL REGISTRATION NUMBER: NCT05574400.

Six-Year Cognitive Trajectory in Older Adults Following Major Surgery and Delirium.

Importance: The study results suggest that delirium is the most common postoperative complication in older adults and is associated with poor outcomes, including long-term cognitive decline and incident dementia. Objective: To examine the patterns and pace of cognitive decline up to 72 months (6 years) in a cohort of older adults following delirium. Design, Setting, and Participants: This was a prospective, observational cohort study with long-term follow-up including 560 community-dwelling older adults (older than 70 years) in the ongoing Successful Aging after Elective Surgery study that began in 2010. The data were analyzed from 2021 to 2022. Exposure: Development of incident delirium following major elective surgery. Main Outcomes and Measures: Delirium was assessed daily during hospitalization using the Confusion Assessment Method, which was supplemented with medical record review. Cognitive performance using a comprehensive battery of neuropsychological tests was assessed preoperatively and across multiple points postoperatively to 72 months of follow-up. We evaluated longitudinal cognitive change using a composite measure of neuropsychological performance called the general cognitive performance (GCP), which is scaled so that 10 points on the GCP is equivalent to 1 population SD. Retest effects were adjusted using cognitive test results in a nonsurgical comparison group. Results: The 560 participants (326 women [58%]; mean [SD] age, 76.7 [5.2] years) provided a total of 2637 person-years of follow-up. One hundred thirty-four participants (24%) developed postoperative delirium. Cognitive change following surgery was complex: we found evidence for differences in acute, post-short-term, intermediate, and longer-term change from the time of surgery that were associated with the development of postoperative delirium. Long-term cognitive change, which was adjusted for practice and recovery effects, occurred at a pace of about -1.0 GCP units (95% CI, -1.1 to -0.9) per year (about 0.10 population SD units per year). Participants with delirium showed significantly faster long-term cognitive change with an additional -0.4 GCP units (95% CI, -0.1 to -0.7) or -1.4 units per year (about 0.14 population SD units per year). Conclusions and Relevance: This cohort study found that delirium was associated with a 40% acceleration in the slope of cognitive decline out to 72 months following elective surgery. Because this is an observational study, we cannot be sure whether delirium directly causes subsequent cognitive decline, or whether patients with preclinical brain disease are more likely to develop delirium. Future research is needed to understand the causal pathway between delirium and cognitive decline.

Successful aging after elective surgery II: Study design and methods.

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.

Neurophysiologic predictors of individual risk for post-operative delirium after elective surgery.

BACKGROUND: Post-surgical delirium is associated with increased morbidity, lasting cognitive decline, and loss of functional independence. Within a conceptual framework that delirium is triggered by stressors when vulnerabilities exist in cerebral connectivity and plasticity, we previously suggested that neurophysiologic measures might identify individuals at risk for post-surgical delirium. Here we demonstrate the feasibility of the approach and provide preliminary experimental evidence of the predictive value of such neurophysiologic measures for the risk of delirium in older persons undergoing elective surgery. METHODS: Electroencephalography (EEG) and transcranial magnetic stimulation (TMS) were collected from 23 patients prior to elective surgery. Resting-state EEG spectral power ratio (SPR) served as a measure of integrity of neural circuits. TMS-EEG metrics of plasticity (TMS-plasticity) were used as indicators of brain capacity to respond to stressors. Presence or absence of delirium was assessed using the confusion assessment method (CAM). We included individuals with no baseline clinically relevant cognitive impairment (MoCA scores ≥21) in order to focus on subclinical neurophysiological measures. RESULTS: In patients with no baseline cognitive impairment (N = 20, age = 72 ± 6), 3 developed post-surgical delirium (MoCA = 24 ± 2.6) and 17 did not (controls; MoCA = 25 ± 2.4). Patients who developed delirium had pre-surgical resting-state EEG power ratios outside the 95% confidence interval of controls, and 2/3 had TMS-plasticity measures outside the 95% CI of controls. CONCLUSIONS: Consistent with our proposed conceptual framework, this pilot study suggests that non-invasive and scalable neurophysiologic measures can identify individuals at risk of post-operative delirium. Specifically, abnormalities in resting-state EEG spectral power or TMS-plasticity may indicate sub-clinical risk for post-surgery delirium. Extension and confirmation of these findings in a larger sample is needed to assess the clinical utility of the proposed neurophysiologic markers, and to identify specific connectivity and plasticity targets for therapeutic interventions that might minimize the risk of delirium.

One-year Medicare costs associated with delirium in older hospitalized patients with and without Alzheimer's disease dementia and related disorders.

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.

Patterns and Persistence of Perioperative Plasma and Cerebrospinal Fluid Neuroinflammatory Protein Biomarkers After Elective Orthopedic Surgery Using SOMAscan.

BACKGROUND: The neuroinflammatory response to surgery can be characterized by peripheral acute plasma protein changes in blood, but corresponding, persisting alterations in cerebrospinal fluid (CSF) proteins remain mostly unknown. Using the SOMAscan assay, we define acute and longer-term proteome changes associated with surgery in plasma and CSF. We hypothesized that biological pathways identified by these proteins would be in the categories of neuroinflammation and neuronal function and define neuroinflammatory proteome changes associated with surgery in older patients. METHODS: SOMAscan analyzed 1305 proteins in blood plasma (n = 14) and CSF (n = 15) samples from older patients enrolled in the Role of Inflammation after Surgery for Elders (RISE) study 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. RESULTS: Comparison of postoperative day 1 (POD1) to preoperative (PREOP) plasma protein levels identified 343 proteins with postsurgical changes ( P < .05; absolute value of the fold change [|FC|] > 1.2). Comparing postoperative 1-month (PO1MO) plasma and CSF with PREOP identified 67 proteins in plasma and 79 proteins in CSF with altered levels ( P < .05; |FC| > 1.2). In plasma, 21 proteins, primarily linked to immune response and inflammation, were similarly changed at POD1 and PO1MO. Comparison of plasma to CSF at PO1MO identified 8 shared proteins. Comparison of plasma at POD1 to CSF at PO1MO identified a larger number, 15 proteins in common, most of which are regulated by interleukin-6 (IL-6) or transforming growth factor beta-1 (TGFB1) and linked to the inflammatory response. Of the 79 CSF PO1MO-specific proteins, many are involved in neuronal function and neuroinflammation. CONCLUSIONS: SOMAscan can characterize both short- and long-term surgery-induced protein alterations in plasma and CSF. Acute plasma protein changes at POD1 parallel changes in PO1MO CSF and suggest 15 potential biomarkers for longer-term neuroinflammation that warrant further investigation.

Parental Education and Delirium Risk after Surgery in Older Adults.

OBJECTIVES: Efforts to conceptualize risk factors for postoperative delirium in older adults have focused on the time proximate to the episode, but how early-life exposures influence delirium risk is poorly understood. METHODS: An observational cohort of 547 patients aged 70+undergoing major non-cardiac surgery at two academic medical centers in Boston. Demographic characteristics, cognition, parental education, health, and participation in cognitively stimulating activities were assessed prior to surgery. Delirium incidence and severity were measured daily during hospitalization. RESULTS: Higher paternal education was associated with significantly lower incidence of delirium (X2(1, N =547)=8.35, p <.001; odds ratio OR=.93, 95% CI, .87 to .98) and inversely associated with delirium severity (r(545)=-.13, p <.001). Higher maternal education was associated with lower delirium incidence but did not reach statistical significance. The effect of paternal education on delirium incidence was independent of the patient's education, estimated premorbid intelligence, medical comorbidities, neighborhood disadvantage, and participation in cognitively stimulating activities (X2(2, N =547)=31.22, p <.001). CONCLUSIONS: Examining early-life exposures may yield unique insights into the risks and pathogenesis of delirium. CLINICAL IMPLICATIONS: Evaluating long-term factors that increase vulnerability to delirium may improve our ability to calculate risk. It may guide clinical decision-making and inform pre- and post-operative recommendations.

Paternal Occupation and Delirium Risk in Older Adults: A Potential Marker of Early-Life Exposures.

Background and Objectives: Delirium is a common disorder among older adults following hospitalization or major surgery. Whereas many studies examine the risk of proximate exposures and comorbidities, little is known about pathways linking childhood exposures to later-life delirium. In this study, we explored the association between paternal occupation and delirium risk. Research Design and Methods: A prospective observational cohort study of 528 older adults undergoing elective surgery at two academic medical centers. Paternal occupation group (white collar vs. blue collar) served as our independent variable. Delirium incidence was assessed using the Confusion Assessment Method (CAM) supplemented by medical chart review. Delirium severity was measured using the peak CAM-Severity score (CAM-S Peak), the highest value of CAM-S observed throughout the hospital stay. Results: Blue-collar paternal occupation was significantly associated with a higher rate of incident delirium (91/234, 39%) compared with white-collar paternal occupation (84/294, 29%), adjusted odds ratio OR (95% confidence interval [CI]) = 1.6 (1.1, 2.3). All analyses were adjusted for participant age, race, gender, and Charlson Comorbidity Index. Blue-collar paternal occupation was also associated with greater delirium severity, with a mean score (SD) of 4.4 (3.3), compared with white-collar paternal occupation with a mean score (SD) of 3.5 (2.8). Among participants reporting blue-collar paternal occupation, we observed an adjusted mean difference of 0.86 (95% CI = 0.4, 1.4) additional severity units. Discussion and Implications: Blue-collar paternal occupation is associated with greater delirium incidence and severity, after adjustment for covariates. These findings support the application of a life-course framework to evaluate the risk of later-life delirium and delirium severity. Our results also demonstrate the importance of considering childhood exposures, which may be consequential even decades later.

Structural integrity of the anterior mid-cingulate cortex contributes to resilience to delirium in SuperAging.

Despite its devastating clinical and societal impact, approaches to treat delirium in older adults remain elusive, making it important to identify factors that may confer resilience to this syndrome. Here, we investigated a cohort of 93 cognitively normal older patients undergoing elective surgery recruited as part of the Successful Aging after Elective Surgery study. Each participant was classified either as a SuperAger (n = 19) or typically aging older adult (n = 74) based on neuropsychological criteria, where the former was defined as those older adults whose memory function rivals that of young adults. We compared these subgroups to examine the role of preoperative memory function in the incidence and severity of postoperative delirium. We additionally investigated the association between indices of postoperative delirium symptoms and cortical thickness in functional networks implicated in SuperAging based on structural magnetic resonance imaging data that were collected preoperatively. We found that SuperAging confers the real-world benefit of resilience to delirium, as shown by lower (i.e. zero) incidence of postoperative delirium and decreased severity scores compared with typical older adults. Furthermore, greater baseline cortical thickness of the anterior mid-cingulate cortex-a key node of the brain's salience network that is also consistently implicated in SuperAging-predicted lower postoperative delirium severity scores in all patients. Taken together, these findings suggest that baseline memory function in older adults may be a useful predictor of postoperative delirium risk and severity and that superior memory function may contribute to resilience to delirium. In particular, the integrity of the anterior mid-cingulate cortex may be a potential biomarker of resilience to delirium, pointing to this region as a potential target for preventive or therapeutic interventions designed to mitigate the risk or consequences of developing this prevalent clinical syndrome.

Identifying Delirium in Persons With Moderate or Severe Dementia: Review of Challenges and an Illustrative Approach.

Delirium and dementia are common causes of cognitive impairment among older adults, which often coexist. Delirium is associated with poor clinical outcomes, and is more frequent and more severe in patients with dementia. Identifying delirium in the presence of dementia, also described as delirium superimposed on dementia (DSD), is particularly challenging, as symptoms of delirium such as inattention, cognitive dysfunction, and altered level of consciousness, are also features of dementia. Because DSD is associated with poorer clinical outcomes than dementia alone, detecting delirium is important for reducing morbidity and mortality in this population. We review a number of delirium screening instruments that have shown promise for use in DSD, including the 4-DSD, combined Six Item Cognitive Impairment Test (6-CIT) and 4 'A's Test (4AT), Confusion Assessment Method (CAM), and the combined UB2 and 3D-CAM (UB-CAM). Each has advantages and disadvantages. We then describe the operationalization of a CAM-based approach in a current ECT in dementia project as an example of modifying an existing instrument for patients with moderate to severe dementia. Ultimately, any instrument modified will need to be validated against a standard clinical reference, in order to fully establish its sensitivity and specificity in the moderate to severe dementia population. Future work is greatly needed to advance the challenging area of accurate identification of delirium in moderate or severe dementia.

Assessment of potential selection bias in neuroimaging studies of postoperative delirium and cognitive decline: lessons from the SAGES study.

Due to cost and participant burden, neuroimaging studies are often performed in relatively small samples of voluntary participants. This may lead to selection bias. It is important to identify factors associated with participation in neuroimaging studies and understand their effect on outcome measures. We investigated the effect of postoperative delirium on long-term (over 48 months) cognitive decline (LTCD) in 560 older surgical patients (≥ 70 years), including a nested MRI cohort (n = 146). We observed a discrepancy in the effect of delirium on cognitive decline as a function of MRI participation. Although overall difference in cognitive decline due to delirium was not greater than what might be expected due to chance (p = .21), in the non-MRI group delirium was associated with a faster pace of LTCD (-0.063, 95% CI -0.094 to -0.032, p < .001); while in the MRI group the effect of delirium was less and not significant (-0.023, 95% CI -0.076, 0.030, p = .39). Since this limits our ability to investigate the neural correlates of delirium and cognitive decline using MRI data, we attempted to mitigate the observed discrepancy using inverse probability weighting for MRI participation. The approach was not successful and the difference of the effect of delirium in slope was essentially unchanged. There was no evidence that the MRI sub-group experienced delirium that differed in severity relative to MRI non-participants. We could not attribute the observed discrepancy to selection bias based on measured factors. It may reflect a power issue due to the smaller MRI subsample or selection bias from unmeasured factors.