scholarly journals Gene-Specific DNA Methylation Linked to Postoperative Cognitive Dysfunction in Apolipoprotein E3 and E4 Mice

2021 ◽  
Vol 83 (3) ◽  
pp. 1251-1268
Author(s):  
Katie J. Schenning ◽  
Sarah Holden ◽  
Brett A. Davis ◽  
Amelia Mulford ◽  
Kimberly A. Nevonen ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cognitive Impairment ◽  
Postoperative Cognitive Dysfunction ◽  
Brain Regions ◽  
Epigenetic Modifications ◽  
Surgical Patients ◽  
Isoflurane Anesthesia ◽  
Genome Wide ◽  
Impaired Cognition ◽  
Postoperative Cognitive Impairment

Background: Geriatric surgical patients are at higher risk of developing postoperative neurocognitive disorders (NCD) than younger patients. The specific mechanisms underlying postoperative NCD remain unknown, but they have been linked to genetic risk factors, such as the presence of APOE4, compared to APOE3, and epigenetic modifications caused by exposure to anesthesia and surgery. Objective: To test the hypothesis that compared to E3 mice, E4 mice exhibit a more pronounced postoperative cognitive impairment associated with differential DNA methylation in brain regions linked to learning and memory. Methods: 16-month-old humanized apolipoprotein-E targeted replacement mice bearing E3 or E4 were subjected to surgery (laparotomy) under general isoflurane anesthesia or sham. Postoperative behavioral testing and genome-wide DNA methylation were performed. Results: Exposure to surgery and anesthesia impaired cognition in aged E3, but not E4 mice, likely due to the already lower cognitive performance of E4 prior to surgery. Cognitive impairment in E3 mice was associated with hypermethylation of specific genes, including genes in the Ephrin pathway implicated in synaptic plasticity and learning in adults and has been linked to Alzheimer’s disease. Other genes, such as the Scratch Family Transcriptional Repressor 2, were altered after surgery and anesthesia in both the E3 and E4 mice. Conclusion: Our findings suggest that the neurocognitive and behavioral effects of surgery and anesthesia depend on baseline neurocognitive status and are associated with APOE isoform-dependent epigenetic modifications of specific genes and pathways involved in memory and learning.

scholarly journals Developmental cannabidiol exposure increases anxiety and modifies genome-wide brain DNA methylation in adult female mice

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Nicole M. Wanner ◽  
Mathia Colwell ◽  
Chelsea Drown ◽  
Christopher Faulk
Keyword(s):  
Dna Methylation ◽  
Molecular Mechanisms ◽  
Coat Color ◽  
Brain Regions ◽  
Functional Enrichment ◽  
Positive Effects ◽  
Genome Wide ◽  
Nulliparous Female ◽  
The Impact ◽  
The Brain

Abstract Background Use of cannabidiol (CBD), the primary non-psychoactive compound found in cannabis, has recently risen dramatically, while relatively little is known about the underlying molecular mechanisms of its effects. Previous work indicates that direct CBD exposure strongly impacts the brain, with anxiolytic, antidepressant, antipsychotic, and other effects being observed in animal and human studies. The epigenome, particularly DNA methylation, is responsive to environmental input and can direct persistent patterns of gene regulation impacting phenotype. Epigenetic perturbation is particularly impactful during embryogenesis, when exogenous exposures can disrupt critical resetting of epigenetic marks and impart phenotypic effects lasting into adulthood. The impact of prenatal CBD exposure has not been evaluated; however, studies using the psychomimetic cannabinoid Δ9-tetrahydrocannabinol (THC) have identified detrimental effects on psychological outcomes in developmentally exposed adult offspring. We hypothesized that developmental CBD exposure would have similar negative effects on behavior mediated in part by the epigenome. Nulliparous female wild-type Agouti viable yellow (Avy) mice were exposed to 20 mg/kg CBD or vehicle daily from two weeks prior to mating through gestation and lactation. Coat color shifts, a readout of DNA methylation at the Agouti locus in this strain, were measured in F1 Avy/a offspring. Young adult F1 a/a offspring were then subjected to tests of working spatial memory and anxiety/compulsive behavior. Reduced-representation bisulfite sequencing was performed on both F0 and F1 cerebral cortex and F1 hippocampus to identify genome-wide changes in DNA methylation for direct and developmental exposure, respectively. Results F1 offspring exposed to CBD during development exhibited increased anxiety and improved memory behavior in a sex-specific manner. Further, while no significant coat color shift was observed in Avy/a offspring, thousands of differentially methylated loci (DMLs) were identified in both brain regions with functional enrichment for neurogenesis, substance use phenotypes, and other psychologically relevant terms. Conclusions These findings demonstrate for the first time that despite positive effects of direct exposure, developmental CBD is associated with mixed behavioral outcomes and perturbation of the brain epigenome.

Postoperative Delirium is Associated with Postoperative Cognitive Dysfunction at One Week after Cardiac Surgery with Cardiopulmonary Bypass

2009 ◽  
Vol 105 (3) ◽  
pp. 921-932 ◽  
Author(s):  
Judith A. Hudetz ◽  
Alison J. Byrne ◽  
Kathleen M. Patterson ◽  
Paul S. Pagel ◽  
David C. Warltier
Keyword(s):  
Cardiac Surgery ◽  
Intensive Care ◽  
Cognitive Impairment ◽  
Cardiopulmonary Bypass ◽  
Cognitive Dysfunction ◽  
Postoperative Delirium ◽  
Postoperative Cognitive Dysfunction ◽  
Surgical Patients ◽  
Nonverbal Memory ◽  
Surgery Group

Postoperative delirium with cognitive impairment frequently occurs after cardiac surgery. It was hypothesized that delirium is associated with residual postoperative cognitive dysfunction in patients after surgery using cardiopulmonary bypass. Male cardiac surgical patients ( M age = 66 yr., SD = 8; M education = 13 yr., SD = 2) and nonsurgical controls ( M age = 62, SD = 7; M education = 12, SD = 2) 55 years of age or older were balanced on age and education. Delirium was assessed by the Intensive Care Delirium Screening Checklist preoperatively and for up to 5 days postoperatively. Recent verbal and nonverbal memory and executive functions were assessed (as scores on particular tests) before and 1 wk. after surgery. In 56 patients studied ( n = 28 Surgery; n=28 Nonsurgery), nine patients from the Surgery group developed delirium. In the Surgery group, the proportion of patients having postoperative cognitive dysfunction was significantly greater in those who experienced delirium (89%) compared with those who did not (37%). The odds of developing this dysfunction in patients with delirium were 14 times greater than those who did not. Postoperative delirium is associated with scores for residual postoperative cognitive dysfunction 1 wk. after cardiac surgery.

scholarly journals Genome-wide Association Study of Postoperative Cognitive Dysfunction in Older Surgical Patients

2020 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Marc Rickenbacher ◽  
Céline S. Reinbold ◽  
Stefan Herms ◽  
Per Hoffmann ◽  
Sven Cichon ◽  
...  
Keyword(s):  
Association Study ◽  
Cognitive Dysfunction ◽  
Genome Wide Association Study ◽  
Postoperative Cognitive Dysfunction ◽  
Genome Wide Association ◽  
Surgical Patients ◽  
Genome Wide

scholarly journals Genome-wide DNA methylation profiling identifies convergent molecular signatures associated with idiopathic and syndromic autism in post-mortem human brain tissue

2019 ◽  
Vol 28 (13) ◽  
pp. 2201-2211 ◽  
Author(s):  
Chloe C Y Wong ◽  
Rebecca G Smith ◽  
Eilis Hannon ◽  
Gokul Ramaswami ◽  
Neelroop N Parikshak ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Temporal Cortex ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Genomic Variation ◽  
Molecular Signatures ◽  
Post Mortem ◽  
Human Brain Tissue ◽  
Genome Wide ◽  
Syndromic Autism

Abstract Autism spectrum disorder (ASD) encompasses a collection of complex neuropsychiatric disorders characterized by deficits in social functioning, communication and repetitive behaviour. Building on recent studies supporting a role for developmentally moderated regulatory genomic variation in the molecular aetiology of ASD, we quantified genome-wide patterns of DNA methylation in 223 post-mortem tissues samples isolated from three brain regions [prefrontal cortex, temporal cortex and cerebellum (CB)] dissected from 43 ASD patients and 38 non-psychiatric control donors. We identified widespread differences in DNA methylation associated with idiopathic ASD (iASD), with consistent signals in both cortical regions that were distinct to those observed in the CB. Individuals carrying a duplication on chromosome 15q (dup15q), representing a genetically defined subtype of ASD, were characterized by striking differences in DNA methylationacross a discrete domain spanning an imprinted gene cluster within the duplicated region. In addition to the dramatic cis-effects on DNA methylation observed in dup15q carriers, we identified convergent methylomic signatures associated with both iASD and dup15q, reflecting the findings from previous studies of gene expression and H3K27ac. Cortical co-methylation network analysis identified a number of co-methylated modules significantly associated with ASD that are enriched for genomic regions annotated to genes involved in the immune system, synaptic signalling and neuronal regulation. Our study represents the first systematic analysis of DNA methylation associated with ASD across multiple brain regions, providing novel evidence for convergent molecular signatures associated with both idiopathic and syndromic autism.

scholarly journals Recent progress towards understanding the role of DNA methylation in human placental development

Reproduction ◽  
2016 ◽  
Vol 152 (1) ◽  
pp. R23-R30 ◽  
Author(s):  
Tina Bianco-Miotto ◽  
Benjamin T Mayne ◽  
Sam Buckberry ◽  
James Breen ◽  
Carlos M Rodriguez Lopez ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Pregnancy Complications ◽  
Large Scale ◽  
Developmental Stages ◽  
Epigenetic Modifications ◽  
Placental Development ◽  
Functional Changes ◽  
Genome Wide

Epigenetic modifications, and particularly DNA methylation, have been studied in many tissues, both healthy and diseased, and across numerous developmental stages. The placenta is the only organ that has a transient life of 9 months and undergoes rapid growth and dynamic structural and functional changes across gestation. Additionally, the placenta is unique because although developing within the mother, its genome is identical to that of the foetus. Given these distinctive characteristics, it is not surprising that the epigenetic landscape affecting placental gene expression may be different to that in other healthy tissues. However, the role of epigenetic modifications, and particularly DNA methylation, in placental development remains largely unknown. Of particular interest is the fact that the placenta is the most hypomethylated human tissue and is characterized by the presence of large partially methylated domains (PMDs) containing silenced genes. Moreover, how and why the placenta is hypomethylated and what role DNA methylation plays in regulating placental gene expression across gestation are poorly understood. We review genome-wide DNA methylation studies in the human placenta and highlight that the different cell types that make up the placenta have very different DNA methylation profiles. Summarizing studies on DNA methylation in the placenta and its relationship with pregnancy complications are difficult due to the limited number of studies available for comparison. To understand the key steps in placental development and hence what may be perturbed in pregnancy complications requires large-scale genome-wide DNA methylation studies coupled with transcriptome analyses.

scholarly journals Epigenetic predictors of lifestyle traits applied to the blood and brain

2020 ◽  
Author(s):  
Danni A. Gadd ◽  
Anna J. Stevenson ◽  
Robert F. Hillary ◽  
Daniel L. McCartney ◽  
Nicola Wrobel ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Prefrontal Cortex ◽  
Brain Region ◽  
Density Lipoprotein ◽  
Brain Regions ◽  
Smoking Behaviour ◽  
Lifestyle Factors ◽  
Target Tissue ◽  
Genome Wide ◽  
The Brain

AbstractModifiable lifestyle factors influence the risk of developing many neurological diseases. These factors have been extensively linked with blood-based genome-wide DNA methylation (DNAm), but it is unclear if the signatures from blood translate to the target tissue of interest - the brain. To investigate this, we apply blood-derived epigenetic predictors of four lifestyle traits to genome-wide DNAm from five post-mortem brain regions and the last blood sample prior to death in 14 individuals in the Lothian Birth Cohort 1936 (LBC1936). Using these matched samples, we found that correlations between blood and brain DNAm scores for smoking, high density lipoprotein (HDL) cholesterol, alcohol and body mass index (BMI) were highly variable across brain regions. Smoking scores in the dorsolateral prefrontal cortex had the strongest correlations with smoking scores in blood (r=0.5, n=14) and smoking behaviour (r=0.56, n=9). This was also the brain region which exhibited the strongest correlations for DNAm at site cg05575921 - the single strongest correlate of smoking in blood - in relation to blood (r=0.61, n=14) and smoking behaviour (r=-0.65, n=9). This suggested a particular vulnerability to smoking-related differential methylation in this region. Our work contributes to understanding how lifestyle factors affect the brain and suggests that lifestyle-related DNAm is likely to be both brain region dependent and in many cases poorly proxied for by blood. Though these pilot data provide a rarely-available opportunity for the comparison of methylation patterns across multiple brain regions and the blood, due to the limited sample size available our results must be considered as preliminary and should therefore be used as a basis for further investigation.Abstract FigureGraphical abstract 203mm x 127mm (DPI 300)Abbreviated summary [50 words]: We apply blood-derived epigenetic signatures of lifestyle traits to matched blood and brain samples, uncovering variability in how well blood translates across brain regions and a relationship between smoking and the prefrontal cortex. Our preliminary results contribute to understanding how lifestyle-related DNA methylation affects the brain in health and disease.

scholarly journals Genome-wide DNA methylation profiling identifies convergent molecular signatures associated with idiopathic and syndromic forms of autism in post-mortem human brain tissue

2018 ◽  
Author(s):  
Chloe C.Y. Wong ◽  
Rebecca G. Smith ◽  
Eilis Hannon ◽  
Gokul Ramaswami ◽  
Neelroop N. Parikshak ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Temporal Cortex ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Genomic Variation ◽  
Molecular Signatures ◽  
Post Mortem ◽  
Human Brain Tissue ◽  
Systematic Analysis ◽  
Genome Wide

AbstractAutism spectrum disorder (ASD) encompasses a collection of complex neuropsychiatric disorders characterized by deficits in social functioning, communication and repetitive behavior. Building on recent studies supporting a role for developmentally moderated regulatory genomic variation in the molecular etiology of ASD, we quantified genome-wide patterns of DNA methylation in 233 post-mortem tissues samples isolated from three brain regions (prefrontal cortex, temporal cortex and cerebellum) dissected from 43 ASD patients and 38 non-psychiatric control donors. We identified widespread differences in DNA methylation associated with idiopathic ASD (iASD), with consistent signals in both cortical regions that were distinct to those observed in the cerebellum. Individuals carrying a duplication on chromosome 15q (dup15q), representing a genetically-defined subtype of ASD, were characterized by striking differences in DNA methylation across a discrete domain spanning an imprinted gene cluster within the duplicated region. In addition to the dramatic cis-effects on DNA methylation observed in dup15q carriers, we identified convergent methylomic signatures associated with both iASD and dup15q, reflecting the findings from previous studies of gene expression and H3K27ac. Cortical co-methylation network analysis identified a number of co-methylated modules significantly associated with ASD that are enriched for genomic regions annotated to genes involved in the immune system, synaptic signalling and neuronal regulation. Our study represents the first systematic analysis of DNA methylation associated with ASD across multiple brain regions, providing novel evidence for convergent molecular signatures associated with both idiopathic and syndromic autism.

scholarly journals Epigenome-wide association study of narcolepsy-affected lateral hypothalamic brains, and overlapping DNA methylation profiles between narcolepsy and multiple sclerosis

SLEEP ◽  
2019 ◽  
Vol 43 (1) ◽  
Author(s):  
Mihoko Shimada ◽  
Taku Miyagawa ◽  
Akari Takeshima ◽  
Akiyoshi Kakita ◽  
Hiromi Toyoda ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Dna Methylation ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Basic Protein ◽  
Temporal Cortex ◽  
Brain Regions ◽  
Genome Wide Association ◽  
Genome Wide ◽  
A Genome

Abstract Narcolepsy with cataplexy is a sleep disorder caused by a deficiency in hypocretin neurons in the lateral hypothalamus (LH). Here we performed an epigenome-wide association study (EWAS) of DNA methylation for narcolepsy and replication analyses using DNA samples extracted from two brain regions: LH (Cases: N = 4; Controls: N = 4) and temporal cortex (Cases: N = 7; Controls: N = 7). Seventy-seven differentially methylated regions (DMRs) were identified in the LH analysis, with the top association of a DMR in the myelin basic protein (MBP) region. Only five DMRs were detected in the temporal cortex analysis. Genes annotated to LH DMRs were significantly associated with pathways related to fatty acid response or metabolism. Two additional analyses applying the EWAS data were performed: (1) investigation of methylation profiles shared between narcolepsy and other disorders and (2) an integrative analysis of DNA methylation data and a genome-wide association study for narcolepsy. The results of the two approaches, which included significant overlap of methylated positions associated with narcolepsy and multiple sclerosis, indicated that the two diseases may partly share their pathogenesis. In conclusion, DNA methylation in LH where loss of orexin-producing neurons occurs may play a role in the pathophysiology of the disease.

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