View details for DOI 10.1016/j.jaclp.2025.10.312

View details for Web of Science ID 001632287200064

Abstract

Delirium is a frequent complication among older adults and is linked to higher mortality, longer hospital stays, and greater healthcare expenditure. Although its clinical relevance is well recognized, routine diagnosis remains challenging because existing tools rely largely on the observation of fluctuating symptoms, which can easily be overlooked in daily practice. Electroencephalography (EEG) provides an objective measure of brain activity, and characteristic changes such as generalized slowing have been consistently described in patients with delirium. Despite these established findings, the conventional EEG setup is technically demanding and not well suited for repeated use in general hospital wards. In recent years, portable point-of-care (POC) EEG systems have been developed, allowing recordings with a limited number of electrodes at the bedside. Several clinical studies have reported that these devices are able to detect delirium with acceptable accuracy, while also offering practical advantages such as rapid deployment and use by non-specialist staff. Among the approaches investigated, the bispectral EEG (BSEEG) method has attracted particular attention. A higher BSEEG score has been shown to correlate with delirium severity and to predict adverse outcomes, including reduced survival, even in patients who did not present with overt clinical symptoms. Beyond the clinical setting, experimental work has applied EEG and BSEEG to rodent models of delirium induced by inflammation or surgery. These studies have highlighted associations between EEG slowing, microglial activation, and behavioral disturbances, suggesting that electrophysiological changes may provide a translational link between basic mechanisms and clinical phenomena. Preclinical data also indicate that BSEEG could serve as a quantitative tool for assessing treatment response in experimental models. Taken together, these findings support the potential of simplified EEG platforms to complement current diagnostic strategies. If further validated in larger, real-world cohorts, bedside EEG may become a practical adjunct for the early recognition of delirium and the monitoring of disease progression, with implications for both patient outcomes and mechanistic research.

View details for DOI 10.1016/j.neurot.2025.e00768

View details for PubMedID 41125492

Abstract

Post-operative delirium (POD) is a common complication after surgery especially in elderly patients, characterized by acute disturbances in consciousness and cognition, which negatively impacts long-term outcomes. Effective treatments remain elusive due to the unclear pathophysiology of POD. To address the knowledge gap, we investigated DNA methylation profiles and gene expression changes in brain cells from POD and non-POD patients who underwent brain resection surgery for medication refractory epilepsy. DNA methylation analysis revealed alteration in epigenetic status of immune and inflammation-related genes. Single-nucleus RNA sequencing (snRNAseq) identified POD-specific glial cell alterations, particularly in microglia, where neuroinflammation was strongly enhanced, consistent with epigenetic findings. Astrocytes exhibited changes in synapse-related functions and migration. Furthermore, downstream analysis indicated similarities between POD-associated glial cell states and pathologies such as encephalitis and dementia. Overall, this study-the first multi-omics analysis of brain tissue from POD patients-provides direct evidence of glial cell contributions to POD pathogenesis, and highlights potential therapeutic targets.

View details for DOI 10.1101/2025.03.13.643155

View details for PubMedID 40161597

View details for PubMedCentralID PMC11952519

Abstract

Delirium is a multifactorial medical condition characterized by impairment across various mental functions and is one of the greatest risk factors for prolonged hospitalization, morbidity, and mortality. Research focused on delirium has proven to be challenging due to a lack of objective measures for diagnosing patients, and few laboratory models have been validated. Our recent studies report the efficacy of bispectral electroencephalography (BSEEG) in diagnosing delirium in patients and predicting patient outcomes. We applied BSEEG to validate a lipopolysaccharide (LPS)-induced mouse model of delirium. Moreover, we investigated the relationship between BSEEG score, delirium-like behaviors, and microglia activation in hippocampal dentate gyrus and cortex regions in young and aged mice. There was a significant correlation between BSEEG score and impairment of attention in young mice. Additionally, there was a significant correlation between BSEEG score and microglial activation in hippocampal dentate gyrus and cortex regions in young and aged mice. We have successfully validated the BSEEG method by showing its associations with a level of behavioral change and microglial activation in an LPS-induced mouse model of delirium. In addition, the BSEEG method was able to sensitively capture an LPS-induced delirium-like condition that behavioral tests could not capture because of a hypoactive state.

View details for DOI 10.1093/gerona/glae261

View details for PubMedID 39492697

Abstract

Delirium is a multifactorial medical condition of waxing and waning impairment across various domains of mental functioning over time. Importantly, delirium is also one of the greatest risk factors for prolonged hospitalization, morbidity, and mortality. Studying this important condition is challenging due to the difficulty in both objective diagnosis in patients and validation of laboratory models. As a result, there is a lack of protective treatments for delirium. Our recent studies report the efficacy of bispectral electroencephalography (BSEEG) in diagnosing delirium in patients and predicting patient outcomes, advancing the concept that this simple measure could represent an additional vital sign for patients. Here, we applied BSEEG to characterize and validate a novel lipopolysaccharide (LPS) mouse model of infection-related delirium. We then applied this model to evaluate the protective efficacy of three putative therapeutic agents: the conventional antipsychotic medication haloperidol, the neuroprotective compound P7C3-A20, and the antibiotic minocycline. Aged mice were more susceptible than young mice to LPS-induced aberration in BSEEG, reminiscent of the greater vulnerability of older adults to delirium. In both young and old mice, P7C3-A20 and minocycline administration prevented LPS-induced BSEEG abnormality. By contrast, haloperidol did not. P7C3-A20 and minocycline have been shown to limit different aspects of LPS toxicity, and our data offers proof of principle that these agents might help protect patients from developing infection-related delirium. Thus, utilization of BSEEG in a mouse model for infection-related delirium can identify putative therapeutic agents for applications in patient clinical trials.

View details for DOI 10.1038/s41398-024-03130-4

View details for PubMedID 39358319

Abstract

Delirium is risky and indicates poor outcomes for patients. Therefore, it is crucial to create an effective delirium detection method. However, the epigenetic pathophysiology of delirium remains largely unknown. We aimed to discover reliable and replicable epigenetic (DNA methylation: DNAm) markers that are associated with delirium including post-operative delirium (POD) in blood obtained from patients among four independent cohorts. Blood DNA from four independent cohorts (two inpatient cohorts and two surgery cohorts; 16 to 88 patients each) were analyzed using the Illumina EPIC array platform for genome-wide DNAm analysis. We examined DNAm differences in blood between patients with and without delirium including POD. When we compared top CpG sites previously identified from the initial inpatient cohort with three additional cohorts (one inpatient and two surgery cohorts), 11 of the top 13 CpG sites showed statistically significant differences in DNAm values between the delirium group and non-delirium group in the same directions as found in the initial cohort. This study demonstrated the potential value of epigenetic biomarkers as future diagnostic tools. Furthermore, our findings provide additional evidence of the potential role of epigenetics in the pathophysiology of delirium including POD.

View details for DOI 10.1038/s41398-024-02986-w

View details for PubMedID 38965205

View details for PubMedCentralID 2698979

Abstract

Delirium, a syndrome characterized by an acute change in attention, awareness, and cognition, is commonly observed in older adults, although there are few quantitative monitoring methods in the clinical setting. We developed a bispectral electroencephalography (BSEEG) method capable of detecting delirium and can quantify the severity of delirium using a novel algorithm. Pre-clinical application of this novel BSEEG method can capture a delirium-like state in mice following LPS administration. However, its application to postoperative delirium (POD) has not yet been validated in animal experiments. This study aimed to create a POD model in mice with the BSEEG method by monitoring BSEEG scores following EEG head-mount implantation surgery and throughout the recovery. We compared the BSEEG scores of C57BL/6J young (2-3 months old) with aged (18-19 months old) male mice for quantitative evaluation of POD-like states. Postoperatively, both groups displayed increased BSEEG scores and a loss of regular diurnal changes in BSEEG scores. In young mice, BSEEG scores and regular diurnal changes recovered relatively quickly to baseline by postoperative day 3. Conversely, aged mice exhibited prolonged increases in postoperative BSEEG scores and it reached steady states only after postoperative day 8. This study suggests that the BSEEG method can be utilized as a quantitative measure of POD and assess the effect of aging on recovery from POD in the pre-clinical model.

View details for DOI 10.1093/gerona/glae158

View details for PubMedID 38877811

Abstract

Delirium is dangerous and a predictor of poor patient outcomes. We have previously reported the utility of the bispectral EEG (BSEEG) with a novel algorithm for the detection of delirium and prediction of patient outcomes including mortality. The present study employed a normalized BSEEG (nBSEEG) score to integrate the previous cohorts to combine their data to investigate the prediction of patient outcomes. We also aimed to test if the BSEEG method can be applicable regardless of age, and independent of delirium motor subtypes.We calculated nBSEEG score from raw BSEEG data in each cohort and classified patients into BSEEG-positive and BSEEG-negative groups. We used log-rank test and Cox proportional hazards models to predict 90-day and 1-year outcomes for the BSEEG-positive and -negative groups in all subjects and motor subgroups.A total of 1,077 subjects, the BSEEG-positive group showed significantly higher 90-day (hazard ratio 1.33 [95% CI 1.16-1.52] and 1-year (hazard ratio 1.22 [95% CI 1.06-1.40] mortality rates than the negative group after adjustment for covariates such as age, sex, CCI, and delirium status. Among patients with different motor subtypes of delirium, the hypoactive group showed significantly higher 90-day (hazard ratio 1.41 [95% CI 1.12-1.76] and 1-year mortality rates (hazard ratio 1.32 [95% CI 1.05-1.67], which remained significant after adjustment for the same covariates.We found that the BSEEG method is capable of capturing patients at high mortality risk.

View details for DOI 10.1016/j.jagp.2023.03.002

View details for PubMedID 37003894

View details for Web of Science ID 000935831100003

View details for Web of Science ID 000892356700006