Oral Papers: Delirium & Agitation
Delirium in elderly patients is common and dangerous. Major risk factors include aging and exogenous insults, such as infection or surgery. Also, neurodegenerative process such as dementia is a risk factor for delirium. In animal models, aging or neurodegenerative process enhance pro-inflammatory cytokine release from microglia in response to exogenous insults. The epigenetic mechanism, especially DNA methylation (DNAm), regulates gene expression and changes with age. Older individuals may have methylation changes that influence the increased cytokine upon insult and the decreased neurotrophic factor, but the degree to which aging affects DNAm of cytokine or neurotrophic genes is not fully understood.
The relationship between aging and DNAm of pro-inflammatory cytokine genes (TNF-alpha, IL1-beta, IL-6) as well as the brain derived neutrophic factor (BDNF) was investigated using methylation array data in three cohorts. Brain and blood samples were collected from a neurosurgery cohort (NSG) of 21 subjects who underwent brain resection. A second cohort, the Grady Trauma Project (GTP), included blood samples from 265 subjects. A third cohort was from the University of Iowa Hospitals and Clinics (UIHC), comparing 45 cases of delirium inpatients and age- and gender- matched controls without delirium.
In the NSG cohort, a significant negative correlation between age and DNAm in brain was found at a CpG in IL-6. With the GTP dataset, significant negative correlations between age and DNAm were seen at most of the CpGs in TNF-alpha. Also, TNF-Alpha expression increases with age. These GTP DNAm correlations in TNF-alpha were also nominally significant in NSG blood samples. In neuronal negative NSG brain tissue, a similar negative trend was observed. With the same GTP dataset, significant positive correlations between age and DNAm were seen at most of the CpGs in BDNF. However, BDNF expression did not show correlation with age. Among UIHC cohort, delirium patients showed negative correlations with age among more CpGs in the TNF-alpha gene than controls, whereas in the BDNF gene, positive correlations with age were observed at more CpGs than controls.
With aging, a decrease in DNAm of cytokines gene CpGs in glia and blood was seen. Also, an increase in DNAm of BDNF gene CpG was seen in blood. Among delirium patients, those correlations were more prevalent than controls. As these changes in DNAm on each gene can affect their expression, additional research is needed to fully elucidate the role of DNAm in aging and how it may influence the pathogenesis of delirium with interaction between inflammation and neurotrophic process.