DNA methylation in the inflammatory genes after neurosurgery and diagnostic ability of post-operative delirium

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Abstract

The pathophysiological mechanisms of postoperative delirium (POD) are still not clear, and no reliable biomarker is available to differentiate those with and without POD. Pre- and post-surgery blood from epilepsy subjects undergoing neurosurgery were collected. DNA methylation (DNAm) levels of the TNF gene, IL1B gene, and IL6 gene by the Illumina EPIC array method, and DNAm levels of the TNF gene by pyrosequencing, were analyzed. Blood from 37 subjects were analyzed by the EPIC array method, and blood from 27 subjects were analyzed by pyrosequencing. Several CpGs in the TNF gene in preoperative blood showed a negative correlation between their DNAm and age both in the POD group and in the non-POD group. However, these negative correlations were observed only in the POD group after neurosurgery. Neurosurgery significantly altered DNAm levels at 17 out of 24 CpG sites on the TNF gene, 8 out of 14 CpG sites on the IL1B gene, and 4 out of 14 CpG sites on the IL6 gene. Furthermore, it was found that the Inflammatory Methylation Index (IMI), which was based on the post-surgery DNAm levels at the selected five CpG sites, can be a potential detection tool for delirium with moderate accuracy; area under the curve (AUC) value was 0.84. The moderate accuracy of this IMI was replicated using another cohort from our previous study, in which the AUC was 0.79. Our findings provide further evidence of the potential role of epigenetics and inflammation in the pathophysiology of delirium.

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Most cited references 26

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Sharon Inouye, Rudi Westendorp, Jane S. Saczynski (2014)

Delirium is an acute disorder of attention and cognition in elderly people (ie, those aged 65 years or older) that is common, serious, costly, under-recognised, and often fatal. A formal cognitive assessment and history of acute onset of symptoms are necessary for diagnosis. In view of the complex multifactorial causes of delirium, multicomponent non-pharmacological risk factor approaches are the most effective strategy for prevention. No convincing evidence shows that pharmacological prevention or treatment is effective. Drug reduction for sedation and analgesia and non-pharmacological approaches are recommended. Delirium offers opportunities to elucidate brain pathophysiology--it serves both as a marker of brain vulnerability with decreased reserve and as a potential mechanism for permanent cognitive damage. As a potent indicator of patients' safety, delirium provides a target for system-wide process improvements. Public health priorities include improvements in coding, reimbursement from insurers, and research funding, and widespread education for clinicians and the public about the importance of delirium. Copyright © 2014 Elsevier Ltd. All rights reserved.

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Delirium is a common problem in the intensive care unit (ICU). Accurate diagnosis is limited by the difficulty of communicating with mechanically ventilated patients and by lack of a validated delirium instrument for use in the ICU. To validate a delirium assessment instrument that uses standardized nonverbal assessments for mechanically ventilated patients and to determine the occurrence rate of delirium in such patients. Prospective cohort study testing the Confusion Assessment Method for ICU Patients (CAM-ICU) in the adult medical and coronary ICUs of a US university-based medical center. A total of 111 consecutive patients who were mechanically ventilated were enrolled from February 1, 2000, to July 15, 2000, of whom 96 (86.5%) were evaluable for the development of delirium and 15 (13.5%) were excluded because they remained comatose throughout the investigation. Occurrence rate of delirium and sensitivity, specificity, and interrater reliability of delirium assessments using the CAM-ICU, made daily by 2 critical care study nurses, compared with assessments by delirium experts using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria. A total of 471 daily paired evaluations were completed. Compared with the reference standard for diagnosing delirium, 2 study nurses using the CAM-ICU had sensitivities of 100% and 93%, specificities of 98% and 100%, and high interrater reliability (kappa = 0.96; 95% confidence interval, 0.92-0.99). Interrater reliability measures across subgroup comparisons showed kappa values of 0.92 for those aged 65 years or older, 0.99 for those with suspected dementia, or 0.94 for those with Acute Physiology and Chronic Health Evaluation II scores at or above the median value of 23 (all P<.001). Comparing sensitivity and specificity between patient subgroups according to age, suspected dementia, or severity of illness showed no significant differences. The mean (SD) CAM-ICU administration time was 2 (1) minutes. Reference standard diagnoses of delirium, stupor, and coma occurred in 25.2%, 21.3%, and 28.5% of all observations, respectively. Delirium occurred in 80 (83.3%) patients during their ICU stay for a mean (SD) of 2.4 (1.6) days. Delirium was even present in 39.5% of alert or easily aroused patient observations by the reference standard and persisted in 10.4% of patients at hospital discharge. Delirium, a complication not currently monitored in the ICU setting, is extremely common in mechanically ventilated patients. The CAM-ICU appears to be rapid, valid, and reliable for diagnosing delirium in the ICU setting and may be a useful instrument for both clinical and research purposes.

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Genome-wide DNA methylation comparison between live human brain and peripheral tissues within individuals

Patricia Braun, Shizhong Han, Benjamin Hing … (2019)

Differential DNA methylation in the brain is associated with many psychiatric diseases, but access to brain tissues is essentially limited to postmortem samples. The use of surrogate tissues has become common in identifying methylation changes associated with psychiatric disease. In this study, we determined the extent to which peripheral tissues can be used as surrogates for DNA methylation in the brain. Blood, saliva, buccal, and live brain tissue samples from 27 patients with medically intractable epilepsy undergoing brain resection were collected (age range 5–61 years). Genome-wide methylation was assessed with the Infinium HumanMethylation450 (n = 12) and HumanMethylationEPIC BeadChip arrays (n = 21). For the EPIC methylation data averaged for each CpG across subjects, the saliva–brain correlation (r = 0.90) was higher than that for blood–brain (r = 0.86) and buccal–brain (r = 0.85) comparisons. However, within individual CpGs, blood had the highest proportion of CpGs correlated to brain at nominally significant levels (20.8%), as compared to buccal tissue (17.4%) and saliva (15.1%). For each CpG and each gene, levels of brain-peripheral tissue correlation varied widely. This indicates that to determine the most useful surrogate tissue for representing brain DNA methylation, the patterns specific to the genomic region of interest must be considered. To assist in that objective, we have developed a website, IMAGE-CpG, that allows researchers to interrogate DNA methylation levels and degree of cross-tissue correlation in user-defined locations across the genome.

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Author and article information

Contributors

Takehiko Yamanashi:

ORCID: http://orcid.org/0000-0002-3881-8997

yamatake@stanford.edu

Gen Shinozaki:

ORCID: http://orcid.org/0000-0001-6129-2789

gens@stanford.edu

Journal

Journal ID (nlm-ta): Transl Psychiatry

Journal ID (iso-abbrev): Transl Psychiatry

Title: Translational Psychiatry

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2158-3188

Publication date (Electronic): 9 December 2021

Publication date PMC-release: 9 December 2021

Publication date Collection: 2021

Volume: 11

Electronic Location Identifier: 627

Affiliations

[1 ]GRID grid.168010.e, ISNI 0000000419368956, Stanford University School of Medicine, Department of Psychiatry and Behavioral Sciences, ; Palo Alto, CA USA

[2 ]GRID grid.214572.7, ISNI 0000 0004 1936 8294, University of Iowa Carver College of Medicine, Department of Psychiatry, ; Iowa City, IA USA

[3 ]GRID grid.265107.7, ISNI 0000 0001 0663 5064, Tottori University Faculty of Medicine, Department of Neuropsychiatry, ; Yonago-shi, Tottori Japan

[4 ]GRID grid.214572.7, ISNI 0000 0004 1936 8294, University of Iowa Carver College of Medicine, Department of Neurosurgery, ; Iowa City, IA USA

[5 ]GRID grid.265050.4, ISNI 0000 0000 9290 9879, Toho University School of Medicine Faculty of Medicine, Department of Neurosurgery (Sakura), ; Sakura-shi, Chiba Japan

[6 ]GRID grid.412807.8, ISNI 0000 0004 1936 9916, Vanderbilt University Medical Center, Department of anesthesiology, ; Nashville, TN USA

[7 ]GRID grid.214572.7, ISNI 0000 0004 1936 8294, University of Iowa Carver College of Medicine, Department of Pathology, ; Iowa City, IA USA

Author information

Takehiko Yamanashi http://orcid.org/0000-0002-3881-8997

Masaaki Iwata http://orcid.org/0000-0002-6143-0181

Gen Shinozaki http://orcid.org/0000-0001-6129-2789

Article

Publisher ID: 1752

DOI: 10.1038/s41398-021-01752-6

PMC ID: 8660911

PubMed ID: 34887385

SO-VID: 67af27f4-f8fe-4410-a9a3-60587b964d69

License:

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