Browsing by Author "Sanders, Robert D."

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    Association between plasma tau and postoperative delirium incidence and severity: a prospective observational study
    (Elsevier, 2021) Ballweg, Tyler; White, Marissa; Parker, Margaret; Casey, Cameron; Bo, Amber; Farahbakhsh, Zahra; Kayser, Austin; Blair, Alexander; Lindroth, Heidi; Pearce, Robert A.; Blennow, Kaj; Zetterberg, Henrik; Lennertz, Richard; Sanders, Robert D.; Medicine, School of Medicine
    Background: Postoperative delirium is associated with increases in the neuronal injury biomarker, neurofilament light (NfL). Here we tested whether two other biomarkers, glial fibrillary acidic protein (GFAP) and tau, are associated with postoperative delirium. Methods: A total of 114 surgical patients were recruited into two prospective biomarker cohort studies with assessment of delirium severity and incidence. Plasma samples were sent for biomarker analysis including tau, NfL, and GFAP, and a panel of 10 cytokines. We determined a priori to adjust for interleukin-8 (IL-8), a marker of inflammation, when assessing associations between biomarkers and delirium incidence and severity. Results: GFAP concentrations showed no relationship to delirium. The change in tau from preoperative concentrations to postoperative Day 1 was greater in patients with postoperative delirium (P<0.001) and correlated with delirium severity (ρ=0.39, P<0.001). The change in tau correlated with increases in IL-8 (P<0.001) and IL-10 (P=0.0029). Linear regression showed that the relevant clinical predictors of tau changes were age (P=0.037), prior stroke/transient ischaemic attack (P=0.001), and surgical blood loss (P<0.001). After adjusting for age, sex, preoperative cognition, and change in IL-8, tau remained significantly associated with delirium severity (P=0.026). Using linear mixed effect models, only tau (not NfL or IL-8) predicted recovery from delirium (P<0.001). Conclusions: The change in plasma tau was associated with delirium incidence and severity, and resolved over time in parallel with delirium features. The impact of this putative perioperative neuronal injury biomarker on long-term cognition merits further investigation.
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    Cohort study into the neural correlates of postoperative delirium: the role of connectivity and slow-wave activity
    (Elsevier, 2020-07) Tanabe, Sean; Mohanty, Rosaleena; Lindroth, Heidi; Casey, Cameron; Ballweg, Tyler; Farahbakhsh, Zahra; Krause, Bryan; Prabhakaran, Vivek; Banks, Matthew I.; Sanders, Robert D.; Medicine, School of Medicine
    Background: Delirium frequently affects older patients, increasing morbidity and mortality; however, the pathogenesis is poorly understood. Herein, we tested the cognitive disintegration model, which proposes that a breakdown in frontoparietal connectivity, provoked by increased slow-wave activity (SWA), causes delirium. Methods: We recruited 70 surgical patients to have preoperative and postoperative cognitive testing, EEG, blood biomarkers, and preoperative MRI. To provide evidence for causality, any putative mechanism had to differentiate on the diagnosis of delirium; change proportionally to delirium severity; and correlate with a known precipitant for delirium, inflammation. Analyses were adjusted for multiple corrections (MCs) where appropriate. Results: In the preoperative period, subjects who subsequently incurred postoperative delirium had higher alpha power, increased alpha band connectivity (MC P<0.05), but impaired structural connectivity (increased radial diffusivity; MC P<0.05) on diffusion tensor imaging. These connectivity effects were correlated (r2=0.491; P=0.0012). Postoperatively, local SWA over frontal cortex was insufficient to cause delirium. Rather, delirium was associated with increased SWA involving occipitoparietal and frontal cortex, with an accompanying breakdown in functional connectivity. Changes in connectivity correlated with SWA (r2=0.257; P<0.0001), delirium severity rating (r2=0.195; P<0.001), interleukin 10 (r2=0.152; P=0.008), and monocyte chemoattractant protein 1 (r2=0.253; P<0.001). Conclusions: Whilst frontal SWA occurs in all postoperative patients, delirium results when SWA progresses to involve posterior brain regions, with an associated reduction in connectivity in most subjects. Modifying SWA and connectivity may offer a novel therapeutic approach for delirium.
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    Post-Operative Delirium and Its Relationship with Biomarkers for Dementia: A Meta-Analysis
    (Cambridge University Press, 2022) Wang, Sophia; Greene, Ryan; Song, Yiqing; Chan, Carol; Lindroth, Heidi; Khan, Sikandar; Rios, Gabriel; Sanders, Robert D.; Khan, Babar; Psychiatry, School of Medicine
    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.
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    Postoperative delirium is associated with increased plasma neurofilament light
    (Oxford University Press, 2020-01) Casey, Cameron P.; Lindroth, Heidi; Mohanty, Rosaleena; Farahbakhsh, Zahra; Ballweg, Tyler; Twadell, Sarah; Miller, Samantha; Krause, Bryan; Prabhakaran, Vivek; Blennow, Kaj; Zetterberg, Henrik; Sanders, Robert D.; Medicine, School of Medicine
    While delirium is associated with cognitive decline and dementia, there is limited evidence to support causality for this relationship. Clarification of how delirium may cause cognitive decline, perhaps through evidence of contemporaneous neuronal injury, would enhance plausibility for a causal relationship. Dose-dependence of neuronal injury with delirium severity would further enhance the biological plausibility for this relationship. We tested whether delirium is associated with neuronal injury in 114 surgical patients recruited to a prospective biomarker cohort study. Patients underwent perioperative testing for changes in neurofilament light, a neuronal injury biomarker, as well as a panel of 10 cytokines, with contemporaneous assessment of delirium severity and incidence. A subset of patients underwent preoperative MRI. Initially we confirmed prior reports that neurofilament light levels correlated with markers of neurodegeneration [hippocampal volume (ΔR2 = 0.129, P = 0.015)] and white matter changes including fractional anisotropy of white matter (ΔR2 = 0.417, P < 0.001) with similar effects on mean, axial and radial diffusivity) in our cohort and that surgery was associated with increasing neurofilament light from preoperative levels [mean difference (95% confidence interval, CI) = 0.240 (0.178, 0.301) log10 (pg/ml), P < 0.001], suggesting putative neuronal injury. Next, we tested the relationship with delirium. Neurofilament light rose more sharply in participants with delirium compared to non-sufferers [mean difference (95% CI) = 0.251 (0.136, 0.367) log10 (pg/ml), P < 0.001]. This relationship showed dose-dependence, such that neurofilament light rose proportionately to delirium severity (ΔR2 = 0.199, P < 0.001). Given that inflammation is considered an important driver of postoperative delirium, next we tested whether neurofilament light, as a potential marker of neurotoxicity, may contribute to the pathogenesis of delirium independent of inflammation. From a panel of 10 cytokines, the pro-inflammatory cytokine IL-8 exhibited a strong correlation with delirium severity (ΔR2 = 0.208, P < 0.001). Therefore, we tested whether the change in neurofilament light contributed to delirium severity independent of IL-8. Neurofilament light was independently associated with delirium severity after adjusting for the change in inflammation (ΔR2 = 0.040, P = 0.038). These data suggest delirium is associated with exaggerated increases in neurofilament light and that this putative neurotoxicity may contribute to the pathogenesis of delirium itself, independent of changes in inflammation.
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    Relationships between preoperative cortical thickness, postoperative electroencephalogram slowing, and postoperative delirium
    (Elsevier, 2021) White, Marissa F.; Tanabe, Sean; Casey, Cameron; Parker, Maggie; Bo, Amber; Kunkel, David; Nair, Veena; Pearce, Robert A.; Lennertz, Richard; Prabhakaran, Vivek; Lindroth, Heidi; Sanders, Robert D.; Medicine, School of Medicine
    Background: It is unclear how preoperative neurodegeneration and postoperative changes in EEG delta power relate to postoperative delirium severity. We sought to understand the relative relationships between neurodegeneration and delta power as predictors of delirium severity. Methods: We undertook a prospective cohort study of high-risk surgical patients (>65 yr old) to identify predictors of peak delirium severity (Delirium Rating Scale-98) with twice-daily delirium assessments (NCT03124303). Participants (n=86) underwent preoperative MRI; 54 had both an MRI and a postoperative EEG. Cortical thickness was calculated from the MRI and delta power from the EEG. Results: In a linear regression model, the interaction between delirium status and preoperative mean cortical thickness (suggesting neurodegeneration) across the entire cortex was a significant predictor of delirium severity (P<0.001) when adjusting for age, sex, and performance on preoperative Trail Making Test B. Next, we included postoperative delta power and repeated the analysis (n=54). Again, the interaction between mean cortical thickness and delirium was associated with delirium severity (P=0.028), as was postoperative delta power (P<0.001). When analysed across the Desikan-Killiany-Tourville atlas, thickness in multiple individual cortical regions was also associated with delirium severity. Conclusions: Preoperative cortical thickness and postoperative EEG delta power are both associated with postoperative delirium severity. These findings might reflect different underlying processes or mechanisms.
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    Reporting Essentials for DElirium bioMarker Studies (REDEEMS): Explanation and Elaboration
    (European Delirium Association, 2022-12-21) Amgarth-Duff, Ingrid; Hosie, Annemarie; Caplan, Gideon A.; Adamis, Dimitrios; Watne, Leiv Otto; Cunningham, Colm; Oh, Esther S.; Wang, Sophia; Lindroth, Heidi; Sanders, Robert D.; Olofsson, Birgitta; Girard, Timothy D.; Steiner, Luzius A.; Vasunilashorn, Sarinnapha M.; Agar, Meera; Psychiatry, School of Medicine
    Despite many studies of potential delirium biomarkers, delirium pathophysiology remains unclear. Evidence shows that the quality of reporting delirium biomarker studies is sub-optimal. Better reporting of delirium biomarker studies is needed to understand delirium pathophysiology better. To improve robustness, transparency and uniformity of delirium biomarker study reports, the REDEEMS (Reporting Essentials for DElirium bioMarker Studies) guideline was developed by an international group of delirium researchers through a three-stage process, including a systematic review, a three-round Delphi study, and a follow-up consensus meeting. This process resulted in a 9-item guideline to inform delirium fluid biomarker studies. To enhance implementation of the REDEEMS guideline, this Explanation and Elaboration paper provides a detailed explanation of each item. We anticipate that the REDEEMS guideline will help to accelerate our understanding of delirium pathophysiology by improving the reporting of delirium biomarker research and, consequently the capacity to synthesise results across studies.