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To identify whether delirium biomarkers aligned with the National Institute on Aging-Alzheimerʼs Association (NIA-AA) research framework, a conceptual model that describes the use of diagnostic biomarkers for Alzheimerʼs disease and other related dementias (ADRD). DESIGN: Systematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. SETTING: Acute care and outpatient settings. PARTICIPANTS: Adults diagnosed with delirium. METHODS AND MEASUREMENTS: MEDLINE, Psy-cInfo, Embase, and the Cochrane Library were searched for English-language studies published from January 2010 to February 2020. Studies included adults older than 18 years, identified delirium with a standardized assessment tool, and measured an ADRD biomarker. Independent reviewers determined whether an association between delirium and ADRD biomarker was found, the quality of biomarker data based on the REMARK (REporting recommendations for tumor MARKer prognostic studies) checklist, and the study bias based on the Newcastle-Ottawa Scale.RESULTS: A total of 61,256 citations were identified; 113 studies were included. Most studies did not examine amyloid, tau, or neurodegeneration biomarkers. Delirium may be associated with neurodegeneration biomarkers, but few to no studies found an association with amyloid and tau biomarkers. Delirium was not consistently associated with inflammatory biomarkers. The quality of biomarker data was moderate, and the risk of bias was moderate to high. Studies often did not collect prehospital and posthospital cognitive data. CONCLUSION: Most delirium diagnostic biomarker studies did not measure amyloid, tau, and/or neurodegenerative biomarkers, making characterization of the relationship between delirium and ADRD difficult. Future delirium biomarker diagnostic studies could improve the understanding of pathophysiologic links between delirium with other conditions affecting cognition.

Objectives This study seeks to identify Alzheimer’s and related dementias (ADRD) biomarkers associated with postoperative delirium (POD) via meta-analysis. Design: A comprehensive search was conducted. Studies met the following inclusion criteria: >18 years of age, identified POD with standardized assessment, and biomarker measured in the AT(N)-X (A = amyloid, T = tau, (N)=neurodegeneration, X-Other) framework. Exclusion criteria: focus on prediction of delirium, delirium superimposed on dementia, other neurologic or psychiatric disorders, or terminal delirium. Reviewers extracted and synthesized data for the meta-analysis. Setting: Meta-analysis. Participants: Patients with POD. Measurements: Primary outcome: association between POD and ATN-X biomarkers. Secondary outcomes involved sample heterogeneity. Results 28 studies were included in this meta-analysis. Studies focused on inflammatory and neuronal injury biomarkers; there were an insufficient number of studies for amyloid and tau biomarker analysis. Two inflammatory biomarkers (IL-6, and CRP) showed a significant relationship with POD (IL-6 n = 10, standardized mean difference (SMD): 0.53, 95% CI: 0.36–0.70; CRP n = 14, SMD: 0.53, 95% CI: 0.33–0.74). Two neuronal injury biomarkers (blood-based S100B and NfL) were positively associated with POD (S100B n = 5, SMD: 0.40, 95% CI: 0.11–0.69; NFL n = 2, SMD: 0.93, 95% CI: 0.28–1.57). Of note, many analyses were impacted by significant study heterogeneity. Conclusions This meta-analysis identified an association between certain inflammatory and neuronal injury biomarkers and POD. Future studies will need to corroborate these relationships and include amyloid and tau biomarkers in order to better understand the relationship between POD and ADRD.

BackgroundDelirium affects nearly 70% of older adults hospitalized in the intensive care unit (ICU), and many of those will be left with persistent cognitive impairment or dementia. There are no effective and scalable recovery models to remediate ICU-acquired cognitive impairment and its attendant elevated risk for dementia or Alzheimer disease (AD). The Improving Recovery and Outcomes Every Day after the ICU (IMPROVE) trial is an ongoing clinical trial which evaluates the efficacy of a combined physical exercise and cognitive training on cognitive function among ICU survivors 50 years and older who experienced delirium during an ICU stay. This article describes the study protocol for IMPROVE.MethodsIMPROVE is a four-arm, randomized controlled trial. Subjects will be randomized to one of four arms: cognitive training and physical exercise; cognitive control and physical exercise; cognitive training and physical exercise control; and cognitive control and physical exercise control. Facilitators administer the physical exercise and exercise control interventions in individual and small group formats by using Internet-enabled videoconference. Cognitive training and control interventions are also facilitator led using Posit Science, Inc. online modules delivered in individual and small group format directly into the participants’ homes. Subjects complete cognitive assessment, mood questionnaires, physical performance batteries, and quality of life scales at baseline, 3, and 6 months. Blood samples will also be taken at baseline and 3 months to measure pro-inflammatory cytokines and acute-phase reactants; neurotrophic factors; and markers of glial dysfunction and astrocyte activation.DiscussionThis study is the first clinical trial to examine the efficacy of combined physical and cognitive exercise on cognitive function in older ICU survivors with delirium. The results will provide information about potential synergistic effects of a combined intervention on a range of outcomes and mechanisms of action.Trial registrationClinicalTrials.gov, NCT03095417. Registered on 23 March 2017. Last updated on 15 May 2017.Electronic supplementary materialThe online version of this article (10.1186/s13063-018-2569-8) contains supplementary material, which is available to authorized users.