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Neurovascular and immune mechanisms that regulate postoperative delirium superimposed on dementia.

ABSTRACT: OBJECTIVE:The present work evaluates the relationship between postoperative immune and neurovascular changes and the pathogenesis of surgery-induced delirium superimposed on dementia. BACKGROUND AND RATIONALE:Postoperative delirium is a common complication in many older adults and in patients with dementia including Alzheimer's disease (AD). The course of delirium can be particularly debilitating, while its pathophysiology remains poorly defined. HISTORICAL EVOLUTION:As of 2019, an estimated 5.8 million people of all ages have been diagnosed with AD, 97% of whom are >65 years of age. Each year, many of these patients require surgery. However, anesthesia and surgery can increase the risk for further cognitive decline. Surgery triggers neuroinflammation both in animal models and in humans, and a failure to resolve this inflammatory state may contribute to perioperative neurocognitive disorders as well as neurodegenerative pathology. UPDATED HYPOTHESIS:We propose an immunovascular hypothesis whereby dysregulated innate immunity negatively affects the blood-brain interface, which triggers delirium and thereby exacerbates AD neuropathology. EARLY EXPERIMENTAL DATA:We have developed a translational model to study delirium superimposed on dementia in APPSwDI/mNos2-/- AD mice (CVN-AD) after orthopedic surgery. At 12 months of age, CVN-AD showed distinct neuroimmune and vascular impairments after surgery, including acute microgliosis and amyloid-β deposition. These changes correlated with attention deficits, a core feature of delirium-like behavior. FUTURE EXPERIMENTS AND VALIDATION STUDIES:Future research should determine the extent to which prevention of surgery-induced microgliosis and/or neurovascular unit dysfunction can prevent or ameliorate postoperative memory and attention deficits in animal models. Translational human studies should evaluate perioperative indices of innate immunity and neurovascular integrity and assess their potential link to perioperative neurocognitive disorders. MAJOR CHALLENGES FOR THE HYPOTHESIS:Understanding the complex relationships between delirium and dementia will require mechanistic studies aimed at evaluating the role of postoperative neuroinflammation and blood-brain barrier changes in the setting of pre-existing neurodegenerative and/or aging-related pathology. LINKAGE TO OTHER MAJOR THEORIES:Non-resolving inflammation with vascular disease that leads to cognitive impairments and dementia is increasingly important in risk stratification for AD in the aging population. The interdependence of these factors with surgery-induced neuroinflammation and cognitive dysfunction is also becoming apparent, providing a strong platform for assessing the relationship between postoperative delirium and longer term cognitive dysfunction in older adults.

SUBMITTER: Wang P

PROVIDER: S-EPMC7317948 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveDelirium superimposed on dementia (DSD) is common in many settings. Nonetheless, little is known about the association between DSD and clinical outcomes. The study aim was to evaluate the association between DSD and related adverse outcomes at discharge from rehabilitation and at 1-year follow-up in older inpatients undergoing rehabilitation.DesignProspective cohort study.SettingHospital rehabilitation unit.ParticipantsA total of 2642 patients aged 65 years or older admitted between January 2002 and December 2006.MeasurementsDementia predating rehabilitation admission was detected by DSM-III-R criteria. Delirium was diagnosed with the DSM-IV-TR. The primary outcome was that of walking dependence (Barthel Index mobility subitem score of <15) captured as a trajectory from discharge to 1-year follow-up. A mixed-effects multivariate logistic regression model was used to analyze the association between DSD and outcome, after adjusting for relevant covariates. Secondary outcomes were institutionalization and mortality at 1-year follow-up, and logistic regression models were used to analyze these associations.ResultsThe median age was 77 years (interquartile range: 71-83). The prevalence of DSD was 8%, and the prevalence of delirium and dementia alone were 4% and 22%, respectively. DSD at admission was found to be significantly associated with almost a 15-fold increase in the odds of walking dependence (odds ratio [OR] 15.5; 95% Confidence Interval [CI] 5.6-42.7; P < .01). DSD was also significantly associated with a fivefold increase in the risk of institutionalization (OR 5.0; 95% CI 2.8-8.9; P < .01) and an almost twofold increase in the risk of mortality (OR 1.8; 95% CI 1.1-2.8; P = .01).ConclusionsDSD is a strong predictor of functional dependence, institutionalization, and mortality in older patients admitted to a rehabilitation setting, suggesting that strategies to detect DSD routinely in practice should be developed and DSD should be included in prognostic models of health care.

Project description:BackgroundHospitalized older adults with preexisting dementia have increased risk of having delirium, but little is known regarding the effect of delirium superimposed on dementia (DSD) on the outcomes of these patients. Our aim was to investigate the association between DSD and hospital mortality and 12-mo mortality in hospitalized older adults.Methods and findingsThis was a prospective cohort study completed in the geriatric ward of a university hospital in São Paulo, Brazil. We included 1,409 hospitalizations of acutely ill patients aged 60 y and over from January 2009 to June 2015. Main variables and measures included dementia and dementia severity (Informant Questionnaire on Cognitive Decline in the Elderly, Clinical Dementia Rating) and delirium (Confusion Assessment Method). Primary outcomes were time to death in the hospital and time to death in 12 mo (for the discharged sample). Comprehensive geriatric assessment was performed at admission, and additional clinical data were documented upon death or discharge. Cases were categorized into four groups (no delirium or dementia, dementia alone, delirium alone, and DSD). The no delirium/dementia group was defined as the referent category for comparisons, and multivariate analyses were performed using Cox proportional hazards models adjusted for possible confounders (sociodemographic information, medical history and physical examination data, functional and nutritional status, polypharmacy, and laboratory covariates). Overall, 61% were women and 39% had dementia, with a mean age of 80 y. Dementia alone was observed in 13% of the cases, with delirium alone in 21% and DSD in 26% of the cases. In-hospital mortality was 8% for patients without delirium or dementia, 12% for patients with dementia alone, 29% for patients with delirium alone, and 32% for DSD patients (Pearson Chi-square = 112, p < 0.001). DSD and delirium alone were independently associated with in-hospital mortality, with respective hazard ratios (HRs) of 2.14 (95% CI = 1.33-3.45, p = 0.002) and 2.72 (95% CI = 1.77-4.18, p < 0.001). Dementia alone did not have a significant statistical association with in-hospital mortality (HR = 1.69, 95% CI = 0.72-2.30, p = 0.385). Finally, while 24% of the patients died after discharge, 12-mo mortality was not associated with dementia or delirium in any of the diagnostic groups (DSD: HR = 1.15, 95% CI = 0.79-1.68, p = 0.463; delirium alone: HR = 1.05, 95% CI = 0.71-1.54, p = 0.810; dementia alone: HR = 1.19, 95% CI = 0.79-1.78, p = 0.399). Limitations to this study include not exploring the effects of the duration and severity of delirium on the outcomes.ConclusionsDSD and delirium alone were independently associated with a worse prognosis in hospitalized older adults. Health care professionals should recognize the importance of delirium as a predictor of hospital mortality regardless of the coexistence with dementia.

Project description:OBJECTIVETo determine whether cognitively stimulating activities would reduce duration and severity of delirium and improve cognitive and physical function to a greater extent than usual care.DESIGNSingle-blind randomized clinical trial.SETTINGEight post-acute care (PAC) facilities.PARTICIPANTSCommunity-dwelling older adults with dementia and delirium (N = 283).INTERVENTIONResearch staff provided cognitively stimulating activities daily for up to 30 days.MEASUREMENTSPrimary outcomes were delirium duration (Confusion Assessment Method) and delirium severity (Delirium Rating Scale). Secondary outcomes were cognitive function (Digits Forward, Montreal Cognitive Assessment, CLOX) and physical function (Barthel Index).RESULTSMean percentage of delirium-free days (intervention: 64.8%, 95% confidence interval (CI) = 59.6-70.1; control: 68.7%, 95% CI = 63.9-73.6; P = .37, Wilcoxon rank sum test) and delirium severity (range 0-39: intervention: 10.77, 95% CI = 10.10-11.45; control: 11.15, 95% CI = 10.50-11.80; difference 0.37, 95% CI = 0.56-1.31, P = .43) were similar in both groups. Significant differences for secondary outcomes favoring intervention were found (executive function (range 0-15): intervention: 6.58, 95% CI = 6.12-7.04; control: 5.89, 95% CI = 5.45-6.33; difference -0.69, 95% CI = 1.33 to -0.06, P = .03; constructional praxis (range 0-15): intervention: 8.84, 95% CI = 8.83-9.34; control: 7.53, 95% CI = 7.04-8.01; difference -1.31, 95% CI = 2.01 to -0.61, P < .001). After adjusting for baseline constructional praxis, the group comparison was no longer significant. Average length of stay was shorter in the intervention (36.09 days) than the control (53.13 days) group (standard error = 0.15, P = .01, negative binomial regression).CONCLUSIONCognitively stimulating activities did not improve delirium but improved executive function and reduced length of stay. Resolution of delirium may require more-intense nonpharmacological management when the individual has dementia.

Project description:ObjectivesDelirium disproportionately affects patients with dementia and is associated with adverse outcomes. The diagnosis of delirium superimposed on dementia (DSD), however, can be challenging due to several factors, including the absence of caregivers or the severity of preexisting cognitive impairment. Altered level of consciousness has been advocated as a possible useful indicator of delirium in this population. Here we evaluated the performance of the Richmond Agitation and Sedation Scale (RASS) and the modified-RASS (m-RASS), an ultra-brief measure of the level of consciousness, in the diagnosis of DSD.DesignMulticenter prospective observational study. RASS and m-RASS results were analyzed together, labeled RASS/m-RASS.SettingAcute geriatric wards, in-hospital rehabilitation, emergency department.ParticipantsPatients 65 years and older with dementia.MeasurementsDelirium was diagnosed with the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) or with the Delirium Rating Scale-Revised (DRS-R-98), or with the 4 A's Test (4AT). Dementia was detected with the Clinical Dementia Rating (CDR) Scale, the Short Form-Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) or via the clinical records.ResultsOf the 645 patients included, 376 (58%) had delirium. According to the instrument used to evaluate delirium, the prevalence was 66% with the 4AT, 23% with the DSM, and 100% with the DRS-R-98. Overall a RASS/m-RASS score other than 0 was 70.5% sensitive (95% confidence interval [CI] 65.9%-75.1%) and 84.8% (CI 80.5%-89.1%) specific for DSD. Using a RASS/m-RASS value greater than +1 or less than -1 as a cutoff, the sensitivity was 30.6% (CI 25.9%-35.2%) and the specificity was 95.5% (CI 93.1%-98.0%). The sensitivity and the specificity did not greatly vary according to the method of delirium diagnosis and the dementia ascertainment, although the specificity was slightly higher when the DSM and the IQCODE were used.ConclusionIn older patients admitted to different clinical settings, the RASS and m-RASS analyzed as a single group had moderate sensitivity and very high specificity for the detection of DSD. Level of consciousness is therefore a valuable clinical indicator that should form part of delirium screening strategies, although for higher sensitivity other methods of assessment should be used.

Project description:Delirium superimposed on dementia (DSD) occurs when patients with pre-existing dementia develop delirium. This complication causes patients to become impaired, posing safety concerns for both hospital staff and patients. Furthermore, there is an increased risk of worsening functional disability and death. Despite medical advances, DSD provides both diagnostic and therapeutic challenges to providers. Identifying at-risk patients and providing personalized medicine and patient care can decrease disease burden in a time-efficient manner. This review delves into bioinformatics-based studies of DSD in order to design and implement a personalized medicine-based approach. Our findings suggest alternative medical treatment methods based on gene-gene interactions, gene-microRNA (miRNA) interactions, gene-drug interactions, and pharmacogenetic variants involved in dementia and psychiatric disorders. We identify 17 genes commonly associated with both dementia and delirium including apolipoprotein E (ApoE), brain-derived neurotrophic factor (BDNF), catechol-O-methyltransferase (COMT), butyrylcholinesterase (BChE), acetylcholinesterase (AChE), DNA methyltransferase 1 (DNMT1), prion protein (PrP), tumor necrosis factor (TNF), serine palmitoyltransferase long chain base subunit 1 (SPTLC1), microtubule-associated protein tau (MAPT), alpha-synuclein (αS), superoxide dismutase 1 (SOD1), amyloid beta precursor protein (APP), neurofilament light (NFL), neurofilament heavy, 5-hydroxytryptamine receptor 2A (HTR2A), and serpin family A member 3 (ERAP3). In addition, we identify six main genes that form an inner concentric model, as well as their associated miRNA. The FDA-approved medications that were found to be effective against the six main genes were identified. Furthermore, the PharmGKB database was used to identify variants of these six genes in order to suggest future treatment options. We also looked at previous research and evidence on biomarkers that could be used to detect DSD. According to research, there are three types of biomarkers that can be used depending on the stage of delirium. The pathological mechanisms underlying delirium are also discussed. This review will identify treatment and diagnostic options for personalized DSD management.

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Neurovascular and immune mechanisms that regulate postoperative delirium superimposed on dementia.

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