Epigenetics of Delirium and Aging: Potential Role of DNA Methylation Change on Cytokine Genes in Glia and Blood Along With Aging

Shinozaki, Gen; Braun, Patricia; Hing, Benjamin; Ratanatharathorn, Andrew; Klisares, Mason J.; Duncan, Gabrielle N.; Jellison, Sydney S.; Heinzman, Jonathan; Nagahama, Yasunori; Close, Liesl N.; Sabbagh, Sayeh; Dlouhy, Brian J.; Howard, Matthew A.; Kawasaki, Hiroto; Cho, Hyunkeun R.

doi:10.3389/fnagi.2018.00311

Cited by 29 publications

(31 citation statements)

References 51 publications

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“…[74][75][76][77][78] Several world leaders in neonatal neurobiology, actively studying the inflammation-induced sensitization paradigm, are expressing grave concern over the increased risk of neurodegeneration following subsequent insults. 87 Furthermore, alteration of DNA methylation by adverse events can lead to discrepancy between chronological age and methylome age, which is associated to accelerated aging processes and age-related pathologies including neurodegenerative diseases and decreased white matter integrity. DNA methylation is a dynamic process that evolves with age and in pathological conditions.…”

Section: F I G U R E 4 Methylation Levels Of Genes Of Interest Associmentioning

confidence: 99%

Alteration of the brain methylation landscape following postnatal inflammatory injury in rat pups

et al. 2019

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This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. contributed equally to this study.Abbreviations: ASD, autism spectrum disorder; CpG, cytosine followed by guanine; DMR, differentially methylated region; DOHaD, developmental origins of health and disease; E. coli, Escherichia coli; GO, gene ontology; LPS, lipopolysaccharide; P3, postnatal day 3; P4, postnatal day 4; P24, postnatal day 24; PBS, phosphate-buffered saline; PFA, paraformaldehyde; RRBS, reduced representation bisulfite sequencing; WMI, white matter injury. AbstractPreterm infants are vulnerable to inflammation-induced white matter injury (WMI), which is associated with neurocognitive impairment and increased risk of neuropsychiatric diseases in adulthood. Epigenetic mechanisms, particularly DNA methylation, play a role in normal development and modulate the response to pathological challenges. Our aims were to determine how WMI triggered DNA methylation alterations in brains of neonatal rats and if such changes persisted over time. We used a robust model of WMI by injecting lipopolysaccharide (LPS) or sterile saline in the corpus callosum of 3-day-old (P3) rat pups. Brains were collected 24 hours (P4) and 21 days post-injection (P24). We extracted genomic DNA from the brain to establish genome-wide quantitative DNA methylation profiles using reduced representation bisulfite sequencing. Neonatal LPS exposure induced a persistent increased methylation of genes related to nervous system development and a reduced methylation of genes associated with inflammatory pathways. These findings suggest that early-life neuroinflammatory exposure impacts the cerebral methylation landscape with determining widespread epigenetic modifications especially in genes related to neurodevelopment. K E Y W O R D SDNA methylation, epigenetics, lipopolysaccharide, periventricular leukomalacia

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Section: F I G U R E 4 Methylation Levels Of Genes Of Interest Associmentioning

confidence: 99%

Alteration of the brain methylation landscape following postnatal inflammatory injury in rat pups

et al. 2019

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“…To fill this gap, we conducted the present study to compare DNAm status in blood from hospitalized patients with and without delirium to identify clinically useful epigenetic biomarkers for delirium from blood samples, which are routinely obtained from patients. We used blood for three reasons: 1) the function of monocytes in the blood is similar to that of microglia in that both release cytokines in response to exogenous stimulus, 2) our comparison of DNAm levels in live brain tissue (resected during neurosurgery) to those in blood from same individual collected at the same time point showed a high level of correlation genome-wide (13), and 3) our previous data showed a similar ageassociated decrease in DNAm in the pro-inflammatory cytokine gene TNF-alpha among glia and blood (12). To accomplish these goals, we conducted the present study investigating DNAm differences in blood between delirium patients and controls without delirium.…”

Section: Introductionmentioning

confidence: 68%

“…This data supports our hypothesis that in pro-inflammatory cytokine genes, DNAm levels decrease along with aging, and expression level increase. In addition, using a unique dataset from our own study comparing DNAm status from neurosurgically resected live human brains followed by fluorescence-activated cell sorting (FACS), we showed that DNAm of the TNF-alpha universally decreases with age among the glial (neuronal negative) component, but no such patterns were found among neurons (neuronal positive component) (12). This data also supports our hypothesis that the DNAm in proinflammatory genes decrease in glia along with aging, making microglia potentially more prone to express those cytokine genes and to have highghtend inflammatory response when exposed to external stimuli such as surgery or infection leading to delirium.…”

Section: Introductionmentioning

confidence: 98%

“…To support this hypothesis of DNAm change along with aging among pro-inflammatory cytokines, we previously reported that DNAm levels in blood decrease along with aging on the pro-inflammatory cytokine gene TNF-alpha, based on 265 participants from the Grady Trauma Project (GTP) (12). We also showed that expression level of TNF-alpha among the same subjects increased with aging (12). This data supports our hypothesis that in pro-inflammatory cytokine genes, DNAm levels decrease along with aging, and expression level increase.…”

Section: Introductionmentioning

confidence: 99%

“…Given the fact that aging and inflammation are the key risk factors of delirium, we focused on the fact that DNA methylation (DNAm) changes dynamically over the human lifespan and that epigenetic mechanisms control the expression of genes including those of cytokines. Thus, we hypothesized that epigenetic modifications specific to aging and delirium susceptibility occur in microglia; that similar modifications occur in blood; and that these epigenetic changes enhance reactions to exogenous insult, resulting in increased cytokine expression and delirium susceptibility (12). In fact, no published study has assessed DNAm and its relationship to delirium in humans, especially with genome-wide DNAm investigation.…”

Section: Introductionmentioning

confidence: 99%

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Epigenetics biomarkers of delirium: immune response, inflammatory response and cholinergic synaptic involvement evidenced by genome-wide DNA methylation analysis of delirious inpatients

Saito

Toda

Duncan³

et al. 2019

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Background: The authors previously hypothesized the role of epigenetics in pathophysiology of delirium, and tested DNA methylation (DNAm) change among pro-inflammatory cytokines along with aging in blood, glia and neuron. The authors reported that DNAm level of the TNF-alpha decreases along with aging in blood and glia, but not in neuron; however, DNAm differences between delirium cases and non-delirium controls have not been investigated directly. Therefore, in the present study, DNAm differences in blood between delirium patients and controls without delirium were examined.Methods: A case-control study with 92 subjects was conducted. Whole blood samples were collected and genome-wide DNAm was measured by the Infinium HumanMethylationEPIC BeadChip arrays. The correlation between DNAm levels in the TNF-alpha and age, network analysis, and the correlation between age and DNAm age were tested.Results: Only delirium cases showed 3 CpGs sites in the TNF-alpha significantly correlated to age after multiple corrections. A genome-wide significant CpG site near the gene of LDLRAD4 was identified. In addition, network analysis showed several significant pathways with false discovery rate adjusted p-value < 0.05. The top pathway with GO was immune response, and the second top pathway with KEGG was cholinergic synapse. Although there was no statistically significant difference, DNAm age among non-delirium controls showed "slower aging" compared to delirium cases.Conclusions: DNAm differences were shown both at gene and network levels between delirium cases and non-delirium controls. This finding indicates that DNAm status in blood has a potential to be used as epigenetic biomarkers for delirium.

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Delirium in neurosurgery: a systematic review and meta-analysis

et al. 2021

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Delirium is a frequent occurring complication in surgical patients. Nevertheless, a scientific work-up of the clinical relevance of delirium after intracranial surgery is lacking. We conducted a systematic review (CRD42020166656) to evaluate the current diagnostic work-up, incidence, risk factors and health outcomes of delirium in this population. Five databases (Embase, Medline, Web of Science, PsycINFO, Cochrane Central) were searched from inception through March 31st, 2021. Twenty-four studies (5589 patients) were included for qualitative analysis and twenty-one studies for quantitative analysis (5083 patients). Validated delirium screening tools were used in 70% of the studies, consisting of the Confusion Assessment Method (intensive care unit) (45%), Delirium Observation Screening Scale (5%), Intensive Care Delirium Screening Checklist (10%), Neelon and Champagne Confusion Scale (5%) and Nursing Delirium Screening Scale (5%). Incidence of post-operative delirium after intracranial surgery was 19%, ranging from 12 to 26% caused by variation in clinical features and delirium assessment methods. Meta-regression for age and gender did not show a correlation with delirium. We present an overview of risk factors and health outcomes associated with the onset of delirium. Our review highlights the need of future research on delirium in neurosurgery, which should focus on optimizing diagnosis and assessing prognostic significance and management.

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Epigenetics of Delirium and Aging: Potential Role of DNA Methylation Change on Cytokine Genes in Glia and Blood Along With Aging

Cited by 29 publications

References 51 publications

Alteration of the brain methylation landscape following postnatal inflammatory injury in rat pups

Alteration of the brain methylation landscape following postnatal inflammatory injury in rat pups

Epigenetics biomarkers of delirium: immune response, inflammatory response and cholinergic synaptic involvement evidenced by genome-wide DNA methylation analysis of delirious inpatients

Delirium in neurosurgery: a systematic review and meta-analysis

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